Imidazolyl-alkenoic acids useful as angiotensin II receptor antagonists

ABSTRACT

Angiotensin II receptor antagonists having the formula: ##STR1## which are useful in regulating hypertension and in the treatment of congestive heart failure, renal failure, and glaucoma, pharmaceutical compositions including these antagonists, and methods of using these compounds to produce angiotensin II receptor antagonism in mammals.

This is a continuation of application Ser. No. 07/954,777, filed Sep.30, 1992, now abandoned, which is a continuation of application Ser. No.07/746,262, filed Aug. 14, 1991 now U.S. Pat. No. 5,185,351, which is acontinuation-in-part of application Ser. No. 07/629,123 filed Dec. 14,1990, now abandoned, which is a continuation-in-part of application Ser.No. 07/506,412 filed Apr. 6, 1990, now abandoned, which is acontinuation-in-part of application Ser. No. 07/366,079 filed Jun. 14,1989, now abandoned.

The present invention relates to new imidazolyl-alkenoic acids which areangiotensin II receptor antagonists and are useful in regulatinghypertension induced or exacerbated by angiotensin II, and in thetreatment of congestive heart failure, renal failure, and glaucoma. Thisinvention also relates to pharmaceutical compositions containing thesecompounds and methods for using these compounds as antagonists ofangiotensin II, as antihypertensive agents and as agents for treatingcongestive heart failure, renal failure, and glaucoma.

BACKGROUND OF THE INVENTION

The class of peptide pressor hormone known as angiotensin is responsiblefor a vasopressor action that is implicated in the etiology ofhypertension in man. Inappropriate activity of the renin-angiotensinsystems appears to be a key element in essential hypertension,congestive heart failure and in some forms of renal disease. In additionto a direct action on arteries and arterioles, angiotensin II (AII),being one of the most potent endogenous vasoconstrictors known, exertsstimulation on the release of aldosterone from the adrenal cortex.Therefore, the renin-angiotensin system, by virtue of its participationin the control of renal sodium handling, plays an important role incardiovascular hemeostasis.

Interruption of the renin-angiotensin system with converting enzymeinhibitors, such as captopril, has proved to be clinically useful in thetreatment of hypertension and congestive heart failure (Abrams, W. B.,et al., (1984), Federation Proc., 43, 1314). The most direct approachtowards inhibition of the renin-angiotensin system would block theaction of AII at the receptor. Compelling evidence suggests that AIIalso contributes to renal vasoconstriction and sodium retention that ischaracteristic of a number of disorders such as heart failure, cirrhosisand complications of pregnancy (Hollenberg, N. K., (1984), J. Cardiovas.Pharmacol., 6, S176). In addition, recent animal studies suggest thatinhibition of the renin-angiotensin system may be beneficial in haltingor slowing the progression of chronic renal failure (Anderson, S., etal., (1985), J. Clin. Invest., 76, 612). Also, a recent patentapplication (South African Patent Application No. 87/01,653) claims thatAII antagonists are useful as agents for reducing and controllingelevated intraocular pressure, especially glaucoma, in mammals.

The compounds of this invention inhibit, block and antagonize the actionof the hormone AII, and are therefore useful in regulating andmoderating angiotensin induced hypertension, congestive heart failure,renal failure and other disorders attributed to the actions of AII. Whencompounds of this invention are administered to mammals, the elevatedblood pressure due to AII is reduced and other manifestations based onAII intercession are minimized and controlled. Compounds of thisinvention are also expected to exhibit diuretic activity.

Recognition of the importance of blocking and inhibiting the actions ofAII has stimulated other efforts to synthesize antagonists of AII. Thefollowing references have disclosed imidazole derivatives which aredescribed as having AII blocking activity and useful as hypotensiveagents.

Furukawa et al., U.S. Pat. No. 4,340,598 discloses imidazol-5-yl-aceticacids and imidazol-5-yl-propanoic acids. Specifically, the discloserincludes 1-benzyl-2-n-butyl-5-chloroimidazole-4-acetic acid and1-benzyl-2-phenyl-5-chloroimidazole-4-propanoic acid.

Furukawa, et al., U.S. Pat. No. 4,355,040 discloses substitutedimidazole-5-acetic acid derivatives. A compound specifically disclosedis 1-(2-chlorobenzyl)-2-n-butyl-4-chloroimidazole-5-acetic acid.

Carini et al. in EP 253,310 disclose certain imidazolylpropenoic acids.Two intermediates described in this patent are ethyl3-[1-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propenoate and ethyl3-[2-butyl-4-chloro-1-(4-aminobenzyl)imidazol-5-yl]propenoate.

Also, Wareing, in PCT/EP 86/00297, discloses as intermediates certainimidazolylpropenoate compounds. On page 62, Formula (CX) is ethyl3-[1(-4-fluorophenyl)-4-isopropyl-2-phenyl-1H-imidazol-5-yl]-2-propenoate.

DESCRIPTION OF THE INVENTION

The compounds of the present invention that are blockers of angiotensinII receptors are represented by the following Formula (I): ##STR2## inwhich:

R¹ is adamantyl, phenyl, biphenyl, or naphthyl, with each aryl groupbeing unsubstituted or substituted by one to three substituents selectedfrom Cl, Br, F, I, C₁ -C₆ alkyl, nitro, A--CO₂ R⁷, tetrazol-5-yl, C₁ -C₆alkoxy, hydroxy, SC₁ -C₆ alkyl, SO₂ NHR⁷, NHSO₂ R⁷, SO₃ H, CONR⁷ R⁷, CN,SO₂ C₁ -C₆ alkyl, NHSO₂ R⁷, PO(OR⁷)₂, NR⁷ R⁷, NR⁷ COH, NR⁷ COC₁ -C₆-alkyl, NR⁷ CON(R⁷)₂, NR⁷ COW, W, SO₂ W;

m is 0-4;

R² is C₂ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₃ -C₆cycloalkyl, or (CH₂)₀₋₈ phenyl unsubstituted or substituted by one tothree substituents selected from C₁ -C₆ alkyl, nitro, Cl, Br, F, I,hydroxy, C₁ -C₆ alkoxy, NR⁷ R⁷, CO₂ R⁷, CN, CONR⁷ R⁷, W, tetrazol-5-yl,NR⁷ COC₁ -C₆ alkyl, NR⁷ COW, SC₁ -C₆ alkyl, SO₂ W, or SO₂ C₁ -C₆ alkyl;

X is a single bond, S, NR⁷, or O;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR⁷, CONR⁷ R⁷, NO₂ ,W, CN, NR⁷ R⁷, or phenyl; 7R7

R⁴ and R⁵ are independently hydrogen, C₁ -C₆ alkyl, thienyl-Y--,furyl-Y--, pyrazolyl-Y--, imidazolyl-Y--, pyrrolyl-Y--, triazolyl-Y--,oxazolyl-Y--, isoxazolyl-Y--, thiazolyl-Y--, pyridyl-Y--, ortetrazolyl-Y--, except that R⁴ and R⁵ are not both selected fromhydrogen and C₁ -C₆ alkyl and each heterocyclic ring is unsubstituted orsubstituted by C₁ -C₆ alkyl, C₁ -C₆ alkoxy, Cl, Br F, I, NR⁷ R⁷, CO₂ R⁷,SO₂ NHR⁷, SO₃ H, or CONR⁷ R⁷, OH, NO₂, W, SO₂ W, SC₁ -C₆ alkyl, SO₂ C₁-C₆ alkyl, NR⁷ COH, NR⁷ COW, or NR⁷ COC₁ -C₆ alkyl;

Y is a single bond, O, S, or C₁ -C₆ alkyl which is straight or branchedor optionally substituted by phenyl or benzyl, wherein each of the arylgroups is unsubstituted or substituted by halo, NO₂, CF₃, C₁ -C₆ alkyl,C₁ -C₆ alkoxy, CN, or CO₂ R⁷ ;

R⁶ is --Z--COOR⁸ or --Z--CONR⁷ R⁷ ;

Z is a single bond, vinyl, --CH₂ --O--CH₂ --, methylene optionallysubstituted by C₁ -C₆ alkyl, one or two benzyl groups, thienylmethyl, orfurylmethyl, or --C(O)NHCHR⁹ --, wherein R⁹ is H, C₁ -C₆ alkyl, phenyl,benzyl, thienylmethyl, or furylmethyl;

W is C_(n) F_(2n+1), C_(n) F_(2n+1), wherein n is 1-3;

A is --(CH₂)_(m) --, --CH═CH--, --O(CH₂)_(n) --, or --S (CH₂)_(n) --;

each R⁷ independently is hydrogen, C₁ -C₆ alkyl, or (CH₂)_(m) phenyl,wherein m is 0-4; and

R⁸ is hydrogen, C₁ -C₆ alkyl, or 2-di(C₁ -C₆ alkyl)-amino-2-oxoethyl; ora pharmaceutically acceptable salt thereof.

Preferably, one of R⁴ and R⁵ is hydrogen or C₁ -C₆ alkyl.

Preferred compounds of this invention are represented by Formula (I)when:

R¹ is phenyl or naphthyl with each aryl group being unsubstituted orsubstituted by one to three substituents selected from chloro, fluoro,trifluoromethyl, nitro, methyl, methoxy, hydroxy, sulfamyl, carboxy,--(CH₂)₁₋₂ carboxy, --CH═CH-carboxy, OCH₂ -carboxy, carboC₁ -C₆ alkoxy,carbamoyl, cyano, or tetrazol-5-yl;

m is 0-2;

X is a single bond or S;

R² is C₂ -C₈ alkyl;

R³ is hydrogen, chloro, fluoro, or trifluoromethyl;

R⁴ is hydrogen or C₁ -C₆ alkyl;

R⁵ is thienylmethyl, thienylethyl, furylmethyl, imidazolylmethyl, orpyridylmethyl, each of which is optionally substituted by methyl ormethoxy; and

R⁶ is COOH, COOC₁₋₂ alkyl, or CONH₂ ; or a pharmaceutically acceptablesalt thereof.

The E isomers (trans stereochemistry of the R⁶ group and imidazolegroup) are generally more active and thus, are preferred over the Zisomers (cis).

As used herein, the terms alkyl, alkenyl, alkoxy and alkynyl mean carbonchains which are branched or unbranched with the length of the chaindetermined by the descriptor preceding the term.

Particular compounds of the invention include, but are not limited to,the following:

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-furyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-pyridyl)methyl-2-propenoic acid,

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-thienyl)methyl-2-propenoic acid,

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-imidazolyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(2-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(2-cyanophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-methoxy-3-methylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methoxy-2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-carboxy-2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-carboxy-3-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-hexyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-carbomethoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-carboxy-2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-propenoic acid,

(E)-3-[2-n-butyl-1-{(3,4-dicarboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)ethyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-carboxymethylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-carboxy-3-hydroxyphenyl)methyl)1H-imidazol-5-yl]-2-(2-thienyl)methyl-2propenoic acid, and

(E)-3-[2-n-butyl-1-{(2-trifluoromethylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid; or a pharmaceutically acceptable salt thereof.

The most preferred compound of this invention is(E)-3-[2-n-butyl-1-{(4-carboxypenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid methanesulfonate.

The invention also relates to pharmaceutical compositions comprising apharmaceutical carrier and an effective amount of a compound of Formula(I).

Also included in the present invention are methods for antagonizingangiotensin II receptors which comprises administering to a subject inneed thereof an effective amount of a compound of Formula (I). Methodsof producing antihypertensive activity and methods of treatingcongestive heart failure, glaucoma, and renal failure by administeringthese compounds are also included in this invention.

The compounds of this invention are prepared by procedures describedherein and illustrated by the examples. Reagents, protecting groups andfunctionality on the imidazole and other fragments of the molecule mustbe consistent with the proposed chemical transformations. Steps in thesynthesis must be compatible with the functional groups and theprotecting groups on the imidazole and other parts of the molecule.

The starting materials, 2-R² X-imidazole, are known to the art (J. Org.Chem. 45:4038, 1980) or are synthesized by known procedures. Forexample, imidazole is converted to 2-n-butylimidazole by reactingimidazole with triethylorthoformate and p-toluenesulfonic acid to give1-diethoxyorthoamide imidazole and then treating with n-butyl lithium togive the 2-lithium derivative of the orthoamide and alkylating withn-butyl iodide in a suitable solvent, such as tetrahydrofuran (THF).

The following procedure is useful for the preparation of compounds ofFormula (I) particularly where R¹ is 2-chlorophenyl or 4-carboxyphenyl,R² is n-butyl or n-propyl, X is a single bond or S, R³ is hydrogen,chloro, or CF₃, R⁴ is hydrogen, R⁵ is as described in Formula (I), R⁶ isCOOR⁸ and R⁸ is hydrogen, methyl, or ethyl.

The 1-R¹ (CH₂)_(m) -group is incorporated onto the 2-R² X-imidazole byknown procedures, for example, by reaction with an R¹ --CH₂ halidemesylate or acetate, such as 2-chlorobenzyl bromide, in a suitablesolvent, such as dimethylformamide (DMF), in the presence of a suitableacid acceptor, such as sodium alkylate, potassium or sodium carbonate,or a metal hydride, preferably sodium hydride at a reaction temperatureof about 25° C. to about 100° C., preferably at about 50° C. Theresulting 1-R¹ (CH₂)_(m) -2-R² X-imidazole is hydroxymethylated in the5-position, for example, by reacting with formaldehyde in the presenceof sodium acetate in acetic acid to provide the 1-R¹ CH₂ -2-R²X-5-hydroxymethylimidazole intermediates.

Alternatively, the 1-R¹ (CH₂)_(m) -2-R² -5-hydroxymethylimidazoleintermediates are prepared by reacting an imido ether, R²--C(═NH)--O-alkyl, such as valeramidine methyl ether, withdihydroxyacetone in liquid ammonia under pressure to give 2-R²-5-hydroxymethylimidazole. This intermediate is reacted with aceticanhydride to give 1-acetyl-5-acetoxymethyl-2-R² -imidazole. Thediacetate intermediate is N-alkylated, for example, using 2-chlorobenzyltriflate and the resulting 1-R¹ (CH₂)_(m) -2-R²-5-acetoxy-methylimidazole is treated with aqueous base, such as 10%sodium hydroxide solution, to give the 1-R¹ (CH₂)_(m) -2-R²-5-hydroxymethylimidazole intermediate.

Alternatively, the 2-R¹ S-imidazole compounds are prepared by thefollowing procedure. Benzylamines, substituted by one to threesubstituents selected from halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, CN, NO₂, CF₃,CO₂ C₁₋₆ alkyl, SC₁₋₆ alkyl, or SO₂ C₁₋₆ alkyl, are alkylated with aC₁₋₆ alkyl chloroacetate, for example methyl chloroacetate, in thepresence of a base, such as triethylamine, in a suitable solvent, suchas dimethylformamide. The resulting alkylaminoalkyl ester compounds areN-formulated with formic acid in the presence of a suitable solvent,such as xylenes, followed by C-formulation of the carbon alpha to boththe amino and the ester groups. Reaction of this intermediate withacidic thiocyanate, preferably potassium thiocyante, in an inert organicsolvent, such as a C₁₋₄ alkyl alcohol, produces 1-RCH₂-2-mercapto-5-alkanoate ester imidazole compounds. The free thio groupof the ester imidazole is reacted with a halo-R¹⁰ compound, wherein R¹⁰is C₂₋₁₀ alkyl, C₃₋₁₀ alkenyl, C₃ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl or anoptionally substituted (CH₂)₀₋₈ phenyl, preferably propyl bromide, inthe presence of a suitable base, such as sodium carbonate, in anappropriate solvent, such as ethyl acetate. The ester is reduced to thehydroxymethylimidazole intermediate by reduction with a suitablereagent, preferably diisobutyl aluminum hydride, in an appropriatesolvent, such as tetrahydrofuran, at a temperature of about -78° C. toabout 25° C., preferably at less than -10° C.

The hydroxymethyl group of the hereinbefore prepared intermediate isoxidized to an aldehyde by treatment with a suitable reagent, such asanhydrous chromic acid-silica gel in tetrahydrofuran or, preferably,with activated manganese dioxide, in a suitable solvent, such as benzeneor toluene, or preferably methylene chloride, at a temperature of about25° C. to about 140° C., preferably at about 25° C. The 1-R¹ (CH₂)_(m)-2-R² X-imidazol-5-carboxaldehydes are reacted with an appropriatephosphonate, such as those listed in Table I (Examples 2-5). Thephosphonates are prepared, for example, from trialkyl phosphonoacetatesby alkylation with an appropriate halide, mesylate or acetate in thepresence of a suitable base, such as sodium hydride, in a suitablesolvent, preferably glyme at a reaction temperature of about 25° C. toabout 110° C., preferably at about 55° C., to provide, for example, thephosphonates listed in Table I. The reaction of theimidazol-5-carboxaldehydes with the phosphonates is performed in thepresence of a suitable base, such as a metal alkoxide, lithium hydrideor preferably sodium hydride, in a suitable solvent, such as ethanol,methanol, ether, dioxane, tetrahydrofuran, or preferably glyme, at areaction temperature of about 10° C. to about 50° C., preferably atabout 25° C., to provide a variable mixture of trans and cis, e.g., (E)and (Z) , 1-R¹ (CH₂)_(m) -2-R² X-5-CH═C(R⁵)-(COOalkyl)-imidazoles. Theseisomers are readily separated by chromatography over silica gel insuitable solvent systems, preferably hexane in ethyl acetate mixtures.The esters are hydrolyzed to the acids, 1-R¹ -(CH₂)_(m) -2-R²X-5-CH═C(R⁵)COOH-imidazoles, using bases, such as potassium hydroxide,lithium hydroxide or sodium hydroxide, in a suitable solvent system,such as, for example, aqueous alcohols or diglyme. The trans and cisstructures of the acids are readily determined by NMR by the NOEprotocol, as well as by the biological activities since, generally, thetrans (E) isomeric acids are the more potent isomers.

Alternatively, the 1-R¹ (CH₂)_(m) -2-R² X-imidazol-5-carboxaldehydes areprepared by the following procedure. Starting 2-R²X-imidazol-5-carboxaldehydes are reacted with an N-alkylating protectingreagent, such as chloromethyl pivalate (POM-Cl), in the presence of abase, such as potassium carbonate, in a suitable solvent, such asdimethylformamide, at a temperature of about 20° C. to about 50° C.,preferably at about 25° C., to give N-alkylation (e.g., POM-derivation)on the least hindered nitrogen atom of the imidazole nucleus. The 1-R¹(CH₂)m-group is incorporated onto the imidazole by N-alkylation of theabove prepared aldehyde with a halomethylbenzene compounds, such asmethyl 4-bromomethyl-3-chlorobenzoate, at a temperature of about 80° C.to about 125° C., preferably at about 100° C. The protecting group onthe 3-nitrogen of the imidazole ring is removed by base hydrolysis, forexample using a biphasic mixture of ethyl acetate and aqueous sodiumcarbonate, to give 1-R¹ CH₂ -2 -R² X-imidazole-5-carboxaldehydecompounds. The Formula (I) compounds can be prepared from these5-carboxaldehyde compounds by the methods described above.

Compounds of Formula (I), wherein R⁶ is COOR⁸, R¹, R², R³, R⁴ and R⁵ areas described in Formula (I) and R⁸ is H, methyl or ethyl, are alsoprepared by the following procedure.

The 2-R² X-imidazole starting materials are reacted withtrimethylsilylethoxymethyl (SEM) chloride to give1-(trimethylsilyl)ethoxymethyl-2-R² X-imidazole. The reaction is carriedout, for example, in the presence of sodium hydride in a solvent such asdimethylformamide. The 5-tributyltin derivatives are prepared bylithiation with, for example, butyllithium in a suitable solvent,preferably diethyl ether, followed by treatment of the lithio imidazolederivative with a tributyltin halide, preferably tri-n-butyltinchloride, at about -10° C. to about 35° C., preferably at about 25° C.The 1-SEM-2-R² X-5-tributyltinimidazole is coupled with anα,β-unsaturated acid ester having a leaving group on the β-position,such as a halide or trifluoromethanesulfonyloxy group, for example,BrCR⁴ ═C(R⁵) (COOalkyl), in the presence of a phosphine ligand, such asbis (diphenyl-phosphino)propane, or triphenylphosphine and a palladium(II) compound, or preferably tetrakis (triphenylphosphine)-palladium(O), with or without a base, such as tributylamine, at atemperature of about 50° C. to about 150° C., preferably at about 120°C. Both the (E) and (Z) olefinic isomers are prepared by this procedure,and the isomeric esters are readily separated by chromatography oversilica gel. The 1-SEM group from the (E) and (Z) isomers is hydrolyzedwith acid, for example, aqueous hydrochloric, in a suitable alcoholicsolvent, such as methanol or ethanol, and the 1-unsubstituted imidazolederivatives are converted to the 1-t-butoxycarbonyl (t-BOC) imidazoleswith di-t-butyl dicarbonate (Hoppe-Seyler's Z. Physiol. Chem., (1976),357, 1651). The t-BOC esters are alkylated and hydrolyzed with, forexample, 2-chlorobenzyl-O-triflate in the presence of a suitable base,preferably diisopropylethylamine, in a suitable solvent, preferablymethylene chloride, to afford the 1-(2-chlorophenyl)methylimidazolederivatives (esters). The (E) and (Z) isomers are hydrolyzed to the (E)and (Z) acids by the method described above.

Compounds of Formula (I) are also prepared by the following procedure.The 1-R¹ (CH₂ )_(m) -2-R² X-imidazole-5-carboxaldehydes, prepared asdescribed above, are reacted with a substituted half-acid, half-esterderivative of a malonate, such as ethyl2-carboxy-3-(2-thienyl)propionate, in the presence of a base, such aspiperidine, in a suitable solvent, such as toluene, at a temperature ofabout 80° C. to about 110° C., preferably at about 100° C. The resulting1-R¹ (CH₂)_(m) -2-R² X-5-CH═C(R⁵) COOalkylimidazoles are hydrolyzed tothe corresponding Formula (I) acid compounds by alkaline hydrolysis asdescribed above.

Compounds of Formula (I) in which R¹ is 2-chlorophenyl or4-carboxyphenyl, R² is n-butyl or n-propyl, X is a single bond or S, R³is H, Cl or CF₃, R⁴ is methyl, R⁵ is as described in Formula (I), R⁶ isCOOR⁸ and other parameters are as described above are prepared asfollows. The 1-R¹ (CH₂)_(m) -2-R² X-imidazol-5-carboxaldehydes, preparedas described above, are converted to the corresponding alcohols with anorgano-metallic derivative or Grignard reagent, preferably methyllithium, in a suitable solvent, such as tetrahydrofuran. The alcohol isoxidized, for example, using manganese dioxide to give the ketone. Theolefinic esters are prepared from the ketone by reaction withappropriate phosphonates to give the (E) and/or (Z) isomers which arereadily separated. The acids are prepared from the esters by alkalinehydrolysis as described above.

Compounds of Formula (I) in which R³ is H, Cl, CH₂ OH, or CF₃ areprepared as follows. The 1-R¹ -(CH₂)_(m) -2-R²X-imidazol-5-carboxaldehydes are treated with the lithium derivative ofa substituted ethyl or methyl ester. These lithio derivatives areprepared from the reaction of lithium diisopropylamide in a suitablesolvent, preferably tetrahydrofuran, with an acid ester, such asROOC--CH₂ --Y-(2-thienyl), to generate the a-lithio derivatives at about-78° C. to about -10° C., preferably at about -78° C., which are thentreated with the imidazol-carboxaldehyde. The intermediate β-hydroxygroup of the imidazole ester is converted to a mesylate or an acetateand the mesylate, or preferably the acetate, is heated in a suitablesolvent, such as toluene, with one to two equivalents of1,8-diazobicyclo[5.4.0]undec-7-ene, at about 50° to about 110° C.preferably at about 80° C., to afford ester compounds of Formula (I)such as 3-(imidazol-5-yl)-2-(2-thienyl)methyl-2-propenoic acid esters.The (E) isomer is the predominate olefinic isomer. The acids areprepared from the esters by the method described above.

Compounds of Formula (I), wherein R¹ is 2-chlorophenyl or4-carboxyphenyl, R² is n-butyl or n-propyl, X is a single bond or S, R³is H, Cl, CF₃, or CH₂ OH, R⁴ is H, R⁵ is heterocyclic or a substitutedheterocyclic group as described in Formula (I) and R⁶ is COOH, may beprepared by heating 1-R¹ --(CH₂)_(m) -2-R² X-imidazol-5-carboxaldehydesat about 50° C. to about 180° C., preferably at about 140° C., with anappropriate substituted heterocyclic acetic acid and with aceticanhydride and potassium carbonate to provide unsaturated acids ofFormula (I), such as3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-R⁵-2-propenoic acid. The trans olefinic acid is the principal product.

Compounds of Formula (I) in which R⁶ is Z--COOR⁸ where Z is anoptionally substituted methylene group are prepared by reducing thetrans or (E) isomers of 3-(imidazol-5-yl)-2-propenoic acid esters(prepared as described above) with an appropriate hydride reagent,preferably diisobutylaluminum hydride, in a suitable solvent, such astetrahydrofuran, to provide the unsaturated alcohol compounds. Thesecompounds are reacted with ethyl chloroformate, for example, with abase, preferably triethylamine, in a suitable solvent, such astetrahydrofuran, to give 5-EtOOCOCH₂ CR⁵ ═CR⁴ -imidazoles which arereacted with carbon monoxide in the presence of a phosphine ligand,preferably triphenyl-phosphine with palladium (II) acetate, in asuitable solvent, preferably tetrahydrofuran, at a temperature of about25° C. to about 100° C., preferably at about 40° C. to give the5-EtOOCCH₂ CR⁵ ═CR⁴ -imidazoles. The corresponding acids are preparedfrom these ethyl esters by base hydrolysis as described above.

Compounds of Formula (I) in which Z is --CH₂ COOR⁸ having additionalsubstitution on the carbon a to the carboxylate group are prepared byconverting 5-EtOOCH₂ CR⁵ ═CH⁴ -imidazoles to the lithium derivative ofthe ester with a lithium dialkylamide, preferably lithiumdiisopropylamide, and then treating with an alkylating agent, such asmethyl halide, benzyl bromide, or heterocyclic methyl halide, to providethe mono-alkylated product compounds or the dialkylated productcompounds. The acid compounds are prepared from the esters by basehydrolysis.

Compounds of Formula (I) in which R⁶ is Z--COOR⁸ where Z is --CH₂--O--CH₂ -- are prepared from unsaturated alcohol compounds, which hadbeen obtained by the reduction of the Formula (I) propenoic acid esters.The alcohol is reacted with an appropriate hydride reagent, such assodium hydride, in a suitable solvent, such as glyme, followed byreaction with an alkylating reagent, such as methyl bromoacetate, togive the 5-MeOOCCH₂ --O--CH₂ CR⁵ ═CR⁴ -imidazoles. The correspondingacids are prepared from these esters by base hydrolysis as describedabove.

Compounds of Formula (I) in which R⁶ is Z--COOR⁸ where Z is --C(O)NHCHR⁹-- are prepared from the Formula (I) propenoic acid compounds. Theseacids are reacted with an appropriately substituted amino acid, such asglycine methyl ester hydrochloride or phenylalanine methyl esterhydrochloride, in the presence of an amide-forming reagent, such asN-hydroxysuccinimide and dicyclohexylcarbodiimide, in the presence of abase, for example triethylamine, in a suitable solvent, such astetrahydrofuran, at a temperature of about 20° C. to about 50° C.,preferably at about 35° C. The 5-C₁₋₄ alkyl-OOCCHR⁹ NHC(O)--CH₂ CR⁵ ═CR⁴-imidazoles are converted to their corresponding acids by basehydrolysis as described above.

Compounds of Formula (I) in which the R¹ substituent is substituted byhydroxy are formed from Formula (I) compounds in which the R¹ group issubstituted by C₁ -C₄ alkoxy using an ether-cleaving reagent, such asboron tribromide or hydrobromic acid.

Compounds of Formula (I) in which the R¹ substituent is substituted bycarboxy are formed from Formula (I) compounds in which the R¹ group issubstituted by CO₂ C₁ -C₄ alkyl using basic hydrolysis, such as aqueoussodium or potassium hydroxide in methanol or ethanol, or using acidichydrolysis, such as aqueous hydrochloric acid.

Compounds of Formula (I) in which the R¹ substituent is substituted by atetrazol-5-yl group are prepared from the correponding carboxycompounds. For example, Formula (I) acid compounds are reacted with ahalogenating agent, such as thionyl chloride, in a suitable solvent, forexample benzene, to give the corresponding acid halide compounds. Theacid halides are then converted to primary amide compounds in a reactionwith concentrated ammonia. Subsequent dehydration of the amides withoxalyl chloride/dimethylformamide in acetonitrile/dimethylformamideyields the nitrile compounds, which are the immediate precursors to theFormula (I) tetrazole compounds. Tetrazole formation is accomplished byreacting the nitriles with azide, preferably aluminum azide prepared insitu by the reaction of sodium azide with aluminum chloride, in asuitable solvent, for example tetrahydrofuran. The Formula (I) compoundsin which R⁶ is --Z--CO₂ H are prepared from these Formula (I) tetrazoleester compounds by basic hydrolysis as described above.

Pharmaceutically acceptable acid addition salts of compounds of Formula(I) are formed with appropriate organic or inorganic acids by methodsknown in the art. For example, the base is reacted with a suitableinorganic or organic acid in an aqueous miscible solvent such as ethanolwith isolation of the salt by removing the solvent or in an aqueousimmiscible solvent when the acid is soluble therein, such as ethyl etheror chloroform, with the desired salt separating directly or isolated byremoving the solvent. Representative examples of suitable acids aremaleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic,palmitic, iraconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric andnitric acids.

Pharmaceutically acceptable base addition salts of compounds of Formula(I) in which R⁸ is H are prepared by known methods from organic andinorganic bases, including nontoxic alkali metal and alkaline earthbases, for example, calcium, lithium, sodium, and potassium hydroxide;ammonium hydroxide, and nontoxic organic bases, such as triethylamine,butylamine, piperazine, meglumine, choline, diethanolamine, andtromethamine.

Angiotensin II antagonist activity of the compounds of Formula (I) isassessed by in vitro and in vivo methods. In vitro antagonist activityis determined by the ability of the compounds to compete with ¹²⁵I-angiotensin II for binding to vascular angiotensin II receptors and bytheir ability to antagonize the contractile response to angiotensin IIin the isolated rabbit aorta. In vivo activity is evaluated by theefficacy of the compounds to inhibit the pressor response to exogenousangiotensin II in conscious rats and to lower blood pressure in a ratmodel of renin dependent hypertension.

Binding

The radioligand binding assay is a modification of a method previouslydescribed in detail (Gunther et al., Circ. Res. 47:278, 1980). Aparticular fraction from rat mesenteric arteries is incubated in Trisbuffer with 80 pM of ¹²⁵ I-angiotensin II with or without angiotensin IIantagonists for 1 hour at 25° C. The incubation is terminated by rapidfiltration and receptor bound ¹²⁵ I-angiotensin II trapped on the filteris quantitated with a gamma counter. The potency of angiotensin IIantagonists is expressed as the IC₅₀ which is the concentration ofantagonist needed to displace 50% of the total specifically boundangiotensin II. Exemplary of the IC₅₀ of compounds of the invention (Eisomers) is about 0.1 nM to about 100 mM.

Aorta

The ability of the compounds to antagonize angiotensin II inducedvasoconstriction is examined in the rabbit aorta. Ring segments are cutfrom the rabbit thoracic aorta and suspended in organ baths containingphysiological salt solution. The ring segments are mounted over metalsupports and attached to force displacement transducers which areconnected to a recorder. Cumulative concentration response curves toangiotensin II are performed in the absence of antagonist or following a30-minute incubation with antagonist. Antagonist disassociationconstants (K_(B)) are calculated by the dose ratio method using the meaneffective concentrations. Exemplary of the K_(B) of compounds of theinvention (E isomers) is about 0.1 nM to about 30 mM.

Inhibition of pressor response to angiotensin II in conscious rats

Rats are prepared with indwelling femoral arterial and venous cathetersand a stomach tube (Gellai et al., Kidney Int. 15:419, 1979). Two tothree days following surgery the rats are placed in a restrainer andblood pressure is continuously monitored from the arterial catheter witha pressure transducer and recorded on a polygraph. The change in meanarterial pressure in response to intravenous injections of 250 mg/kgangiotensin II is compared at various time points prior to and followingthe administration of the compounds intravenously or orally at doses of0.1 to 300 mg/kg. The dose of compound needed to produce 50% inhibitionof the control response to angiotensin II (IC₅₀) is used to estimate thepotency of the compounds. The IC₅₀ of(E)-3-[2-n-butyl-1-{(2-chlorophenyl)-methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid is 3.60 mg/kg i.v. and 44.00 mg/kg orally.

Antihypertensive activity

The antihypertensive activity of the compounds is measured by theirability to reduce mean arterial pressure in conscious rats maderenin-dependent hypertensive by ligation of the left renal artery(Cangiano et al., J. Pharmacol. Exp. Ther. 208:310, 1979). Renal arteryligated rats are prepared with indwelling catheters as described above.Seven to eight days following renal artery ligation, the time at whichplasma renin levels are highest, the conscious rats are placed inrestrainers and mean arterial pressure is continuously recorded prior toand following the administration of the compounds intravenously ororally. The dose of compound needed to reduce mean arterial pressure by30 mm Hg (IC₃₀) is used as an estimate of potency. The IC₃₀ of(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid is 1.80 mg/kg i.v. and 8.0 mg/kg orally.

The intraocular pressure lowering effects employed in this invention maybe measured by the procedure described by Watkins, et al., J. OcularPharmacol., 1 (2):161-168 (1985).

The compounds of Formula (I) are incorporated into convenient dosageforms, such as injectable preparations, or for orally active compounds,capsules or tablets. Solid or liquid pharmaceutical carriers areemployed. Solid carriers include starch, lactose, calcium sulfatedihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate, and stearic acid. Liquid carriers include syrup,peanut oil, olive oil, saline, and water. Similarly, the carrier ordiluent may include any prolonged release material, such as glycerylmonostearate or glyceryl distearate, alone or with a wax. The amount ofsolid carrier varies widely but, preferably, will be from about 25 mg toabout 1 g per dosage unit. When a liquid carrier is used, thepreparation will be in the form of a syrup, elixir, emulsion, softgelatin capsule, sterile injectable liquid, such as an ampoule, or anaqueous or nonaqueous liquid suspension.

For topical ophthalmolgic administration, the pharmaceuticalcompositions adapted include solutions, suspensions, ointments, andsolid inserts. Typical pharmaceutically acceptable carriers are, forexample, water, mixtures of water and water-miscible solvents such aslower alkanols or vegetable oils, and water soluble ophthalmologicallyacceptable non-toxic polymers, for example, cellulose derivatives suchas methyl cellulose. The pharmaceutical preparation may also containnon-toxic auxiliary substances such as emulsifying, preserving, wetting,and bodying agents, as for example, polyethylene glycols; antibacterialcomponents, such as quarternary ammonium compounds; bufferingingredients, such as alkali metal chloride; antioxidants, such as sodiummetabisulfite; and other conventional ingredients, such as sorbitanmonolaurate.

Additionally, suitable ophthalmic vehicles may be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems.

The pharmaceutical preparation may also be in the form of a solidinsert. For example, one may use a solid water soluble polymer as thecarrier for the medicament. Solid water insoluble inserts, such as thoseprepared from ethylene vinyl acetate copolymer, may also be utilized.

The pharmaceutical preparations are made following conventionaltechniques of a pharmaceutical chemist involving mixing, granulating,and compressing, when necessary, for tablet forms, or mixing, fillingand dissolving the ingredients, as appropriate, to give the desiredoral, parenteral, or topical products.

Doses of the compounds of Formula (I) in a pharmaceutical dosage unit asdescribed above will be an efficacious, nontoxic quantity selected fromthe range of 0.01-200 mg/kg of active compound, preferably 1-100 mg/kg.The selected dose is administered to a human patient in need ofangiotensin II receptor antagonism from 1-6 times daily, orally,rectally, topically, by injection, or continuously by infusion. Oraldosage units for human administration preferably contain from 1 to 500mg of active compound. Preferably, lower dosages are used for parenteraladministration. Oral administration, at higher dosages, however, alsocan be used when safe and convenient for the patient. Topicalformulations contain the active compound in an amount selected from0.0001 to 0.1 (w/v %), preferably from 0.0001 to 0.01. As a topicaldosage unit form, an amount of active compound from between 50 ng to0.05 mg, preferably 50 ng to 5 mg, is applied to the human eye.

The method of this invention of antagonizing angiotensin II receptors inmammals, including humans, comprises administering to a subject in needof such antagonism an effective amount of a compound of Formula (I). Themethod of this invention of producing antihypertensive activity and themethod of treating congestive heart failure, glaucoma, and renal failurecomprise administering a compound of Formula (I) to a subject in needthereof an effective amount to produce said activity.

Contemplated equivalents of Formula (I) compounds are compoundsotherwise corresponding thereto wherein substituents have been added toany of the unsubstituted positions of the Formula (I) compounds providedsuch compounds have the pharmaceutical utility of Formula (I) compounds.

The following examples illustrate preparation of compounds andpharmaceutical compositions of this invention. The examples are notintended to limit the scope of this invention as defined hereinabove andas claimed below.

EXAMPLE 1(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

(i) 2-n-butyl-1-(2-chloro-phenyl)methyl-1H-imidazole

Imidazole was converted to the 1-diethoxyorthoamide derivative by themethod of Curtis and Brown, J. Org. Chem., (1980), 45, 20. Imidazole(12.8 g, 0.19 mol) and 118.4 g (0.8 mol) of triethylorthoformate werereacted in the presence of 1 g of p-toluenesulfonic acid to give 20.6(61%), bp 65°-70° C. (0.1 mm) of 1-diethoxyorthoamide imidazole. Thisproduct (24.0 g, 0.14 mol) was dissolved in dry tetrahydrofuran (250mL), cooled to -40° C. and n-butyl lithium (0.14 mol, 56.4 mL of 2.5M inhexane) was added at -40° C. to -35° C. After 15 minutes n-butyl iodide(31.1 g, PG,22 0.169 mol) was added at -40° C. and the reaction wasstirred overnight at ambient temperature. The reaction was partitionedbetween ether and 0.3N hydrochloric acid, and the organic layer wasrepeatedly extracted with dilute hydrochloric acid. The combined aqueousextracts were neutralized with sodium bicarbonate solution, extractedwith methylene chloride, dried over magnesium sulfate and concentrated.A flash distillation on a Kugelrohr apparatus provided 14.8 g (85%) of2-n-butylimidazole.

2-n-Butylimidazole (9.7 g, 0.078 mol) was dissolved in methanol (50 mL)and added dropwise to a solution of sodium methoxide (from sodiumhydride (2.31 g, 0.0934 mol) in methanol (250 mL)). After one hour thesolution was evaporated to dryness, and the sodium salt was taken up indry dimethylformamide (150 mL) and 2-chlorobenzyl bromide (16.3 g, 0.079mol) was added. The mixture was heated at 50° C. for 17 hours underargon, poured onto ice water and the product was extracted into ethylacetate. The extract was washed, dried, and concentrated to give 18.5 gof crude product which was chromatographed over silica gel with 2:1ethyl acetate/hexane to provide 11.9 g (61%) of2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole as an oil. Thin layerchromatography on silica gel with 4:1 ethyl acetate/hexane gave an R_(f)value of 0.59.

(ii) 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole

Method 1

A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole (95.5 g,0.384 mol), 37% formaldehyde (500 mL), sodium acetate (80 g) and aceticacid (60 mL) was heated to reflux for 40 hours under argon. The reactionwas concentrated in vacuo, and the residue was stirred with 500 mL of20% sodium hydroxide solution for 4 hours, diluted with water andextracted with methylene chloride. The extract was washed, dried, andconcentrated. The crude product (117 g) was flash chromatographed over600 g of silica gel with a gradient of ethyl acetate to 10% of methanolin ethyl acetate to give 8.3 g of starting material, 24.5 g of a mixtureof starting material and product, and 44 g (41%) of2-n-butyl-1-(2-chlorophenyl)-methyl-5-hydroxymethyl-1H-imidazole; mp86°-88° C. (from ethyl acetate). Further elution provided the bis(4,5-hydroxymethyl) derivative; mp 138°-140° C. (from ethyl acetate).

Method 2

A mixture of valeramidine methyl ether hydrochloride (250 g, 1.66 mol)and dihydroxyacetone (150 g, 0.83 mol) dissolved in liquid ammonia wasallowed to stand overnight at room temperature in a pressure vessel, andthen heated at 65° C. for 4 hours at 375 psi. The ammonia was allowed toevaporate, and the residue was dissolved in methanol (3L). The resultingslurry was refluxed with added acetonitrile (1L). The solution wasdecanted from the solid ammonium chloride while hot. This procedure wasrepeated, and the combined acetonitrile extracts were treated withcharcoal, filtered hot and the filtrate was concentrated in vacuum togive the dark oil, 2-n-butyl-5-hydroxymethylimidazole (253 g, 1.63 mol,98%).

This crude alcohol (253 g) was treated with acetic anhydride (400 mL) at-15° C. and then was allowed to warm to ambient temperature withstirring, and then stirred an additional 19 hours. The acetic anhydridewas evaporated at reduced pressure, the residue taken up in methylenechloride, and the organic phase was washed with 5% sodium bicarbonatesolution and water. The extract was dried over sodium sulfate andconcentrated to give 323 g (83%) of1-acetyl-4-acetoxymethyl-2-n-butylimidazole.

This diacetate was N-alkylated by the following procedure. To a solutionof triflic anhydride (120 mL, 0.71 mol) in methylene chloride (200 mL)at -78° C. under argon was added a solution of diisopropyl ethylamine(128 mL, 0.73 mol) and 2-chlorobenzyl alcohol (104 g, 0.72 mol) inmethylene chloride (350 mL) over a period of 20 minutes. After beingstirred an additional 20 minutes at -78° C., this solution was thentreated with 1-acetyl-4-acetoxymethyl-2-n-butylimidazole (146 g, 0.61mol) dissolved in methylene chloride (300 mL) over a 20-minute interval.The mixture was then stirred at ambient temperature for 18 hours and thesolvents were evaporated, The residual2-n-butyl-5-acetoxymethyl-1-(2-chlorophenyl)methyl-1H-imidazole was usedwithout purification for the hydrolysis of the acetate group.

A solution of crude2-n-butyl-5-acetoxymethyl-1-(2-chlorophenyl)methyl-1H-imidazole (250 g)in methanol (200 mL) was treated with 10% sodium hydroxide solution (700mL) and the mixture was heated on a steam bath for 4 hours. Aftercooling, methylene chloride was added, the organic phase was separated,washed with water, dried and concentrated. The residue was dissolved inether, cooled, and seeded to give the crude product. Recrystallizationfrom ethyl acetate gave 176 g of2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp86°-88° C. This material was identical in all respects to the productprepared by Method 1.

(iii) 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde

A solution of2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (5.4 g,0.0194 mol) in toluene (25 mL) was added to a suspension of activatedmanganese dioxide (27 g) in methylene chloride (325 mL). The suspensionwas stirred at room temperature for 17 hours. The solids were filteredand the filtrate concentrated and flash chromatographed over silica gelwith 6:4 hexane/ethyl acetate to afford 4.16 g (78%) of2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde, as anoil. NMR and IR were consistent with the structure.

(iv)(E)-3-[2-n-butyl-1-{(2-chloropheny)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid

Method A

(a) trimethyl 3-(2-thienyl)-2-phosphonopropionate

To a solution of 2-thiophenemethanol (2.28 g, 0.02 mol) in carbontetrachloride (25 mL) was added triphenylphosphine (6.81 g, 0.026 mol),and the solution was refluxed for 3 hours. The cooled reaction mixturewas diluted with hexane (60 mL), chilled and filtered. The concentratedfiltrate (4.6 g) was flash chromatographed over silica gel with 7:3hexane/ethyl acetate to provide 2-chloromethylthiophene (1.52 g, 57%) asan oil.

A suspension of sodium hydride (0.271 g, 11.3 mmol) in dry glyme (40 mL)under argon was treated dropwise with trimethyl phosphonoacetate (1.87g, 10.3 mmol) in glyme (5 mL). The resulting mixture was stirred at roomtemperature for 1.5 hours. Then 2-chloromethyl-thiophene (1.5 g, 11.3mmol) was added, and the mixture was stirred at 65° C. for 18 hours. Thereaction was partitioned between water and ethyl acetate, and theorganic layer was washed with water and brine, dried with anhydrousmagnesium sulfate and concentrated to 1.9 g of an oil. This waschromatographed over silica gel 4:1 ethylacetate/hexane to afford 800 mg(28%) of trimethyl 3-(2-thienyl)-2-phosphonopropionate.

(b) methyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl-2-(2-thienyl)methyl-2-propenoate

To a suspension of sodium hydride (69 mg, 2.87 mmol) in glyme (5 mL) wasadded dropwise a solution of trimethyl3-(2-thienyl)-2-phosphonopropionate in glyme (3 mL) under an atomsphereof argon. When the gas evolution had subsided, the mixture was heated to50° C. for 15 minutes. A solution of2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5 -carboxaldehyde (0.53g, 1.92 mmol) in glyme (3 mL) was added, and the mixture was stirred at60°-65° C. for 5 hours. The cooled reaction was partitioned betweenwater and ethyl acetate, and the organic layer was washed with water,dried, concentrated and flash chromatographed over silica gel to give336 mg (41%) of methyl(E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl[-2-(2-thienyl)methyl-2-propenoateas an oil whose NMR was entirely consistent with the trans or E form ofthe olefin.

(c)(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid

A solution of methyl(E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate(336 mg, 0.783 mmol) in ethanol (10 mL) was treated with 10% sodiumhydroxide solution (4 mL), and the solution was stirred for 3 hours at25° C. The pH was adjusted to 5 and a solid precipitated. The mixturewas diluted with water, cooled and filtered to provide 309 mg of solid.A crystallization from ethyl acetate gave 195 mg (60%) of(E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid; mp 177°-179° C.

Method B

(a) methyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-3-hydroxy-2-(2-thienyl)methylpropanoate

To a solution of diisopropylamine (1.96 g, 0.0194 mol) in drytetrahydrofuran (40 mL) held at -78° C. under argon was added n-butyllithium (7.3 mL, 0.0183 mol of 2.5M in toluene), and the mixture wasstirred for 10 minutes. Then, methyl 3-(2-thienyl) propanoate (2.83 g,0.0166 mol) in tetrahydrofuran (2 mL) was added, and the mixture wasstirred for 30 minutes at -78° C. A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (3 g, 0.0111 mol)in tetrahydrofuran (4 mL) was added, and the resulting mixture wasstirred at -78° C. for 30 minutes. The reaction was partitioned betweensaturated ammonium chloride solution and ether, the organic extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated to 6.67 g of crude product. This was flash chromatographedover 70 g of silica gel with 4:1 ethyl acetate/hexane to provide 4.03 g(81%) of methyl3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-(2-thienyl)methyl-propanoate.

(b) methyl3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(2-thienyl)methylpropanoate

A solution of methyl 3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-(2-thienyl)-methylpropanoate (4.03g, 9.02 mmol) in methylene chloride (100 mL) was treated with4-dimethylaminopyridine (0.386 g, 3.16 mmol). Then acetic anhydride (8.5mL, 9.02 mmol) was added dropwise to the stirred mixture. The mixturewas stirred for 18 hours, water (35 mL) was added, the mixture wasstirred for 1 hour and then diluted with ether and saturated sodiumbicarbonate solution. The ether layer was washed with brine, dried withanhydrous magnesium sulfate and evaporated to give the title 3-acetoxyderivative as an oil (4.37 g, 99%).

(c) methyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate

A mixture of methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(2-thienyl)methylpropanoate (4.36 g, 8.92mmol) in dry toluene (80 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.2 mL, 21.4 mmol), and the resulting solution washeated at 80° C. under argon for 3 hours. The solvent was evaporated,the residue triturated with ether and activated charcoal was added.After filtration, the filtrate was concentrated to 6.29 g of an oil thatwas chromatographed over silica gel with 65:35 hexane/ethyl acetate togive 2.89 g (76%) of methyl(E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl]-2-(2-thienyl)-methyl-2-propenoatewhose NMR and TLC (50% ethyl acetate in hexane on silica gel) wereidentical to the product prepared by Method A.

(d)(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid

Basic hydrolysis of this ester (2.88 g, 6.71 mmol) according to Method A(iii) gave 2.59 g (93%) of(E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid; mp 175°-177° C. that was identical to the product from Method A.

EXAMPLES 2-5

In Table I are listed other examples of alkenoic acids prepared from2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde by themethods described in Example 1 (Method A). The reagents and products areshown in Table I.

                                      TABLE I                                     __________________________________________________________________________    Alkenoic Acids                                                                                                       Products (percentage yield)             Example                                                                             Reactant.sup.b    R   R.sup.1                                                                                  ##STR3##                                                                                  ##STR4##                  __________________________________________________________________________    1     (MeO).sub.2 P(O)CH(CH.sub.2 -2-thienyl)- COOMe.sup.c                                            Me H                                                                               ##STR5##  oil mp 177-179° C.                                                                 -- --                      2     (MeO).sub.2 P(O)CH(CH.sub.2 -2-furyl)- COOMe.sup.c                                              Me H                                                                               ##STR6##  oil (38) mp 180.5-182° C.                                              (73)        oil (21) mp                                                                   134.5-136° C.                                                          (38)                       3     (MeO).sub.2 P(O)CH(CH.sub.2 -3-furyl) COOMe.sup.c                                               Me H                                                                               ##STR7##  oil (39) mp 167.5-169° C.                                              (57)        oil (24) --                4     (MeO).sub.2 P(O)CH(CH.sub.2 -4-(1-tosyl) imidazole)COOMe.sup.c                                  Me H                                                                               ##STR8##  oil mp 230-231° C.                                                                 -- --                      5     (MeO).sub.2 P(O)CH(CH.sub.2 -3-thienyl)- COOMe.sup.c                                            Me H                                                                               ##STR9##  oil (50) mp 192-193.5° C.                                              (74)        oil (38) mp                                                                   128.5-130° C.                                                          (48)                       __________________________________________________________________________     ##STR10##                                                                     .sup.b Prepared as in c;                                                      .sup.c Reactants for 2-5 prepared as in Method A(i), Example 1 except         2chloromethylfuran, 3chloromethylfuran, 4acetoxymethyl-1-tosylimidazole,      and 3chloromethylthiophene are used in place of 2chloromethylthiophene.  

EXAMPLE 6 (E andZ)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl)}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoicAcid

Method A

To a suspension of sodium hydride (0.02 mol) in glyme (30 mL) is addeddropwise under argon trimethyl3-(5-methyl-2-furyl)-2-phosphonopropionate (0.02 mol). After one hour atambient temperature, 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (0.0137 mol) is added, and themixture is stirred at 40° C. for one hour. The reaction is quenched withice water, the product extracted into ether and solvent evaporated togive methyl(E)-3-[2-n-butyl-1{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoate.The (E) ester is dissolved in ethanol (4 mL) and 10% sodium hydroxidesolution (0.5 mL) is added. The solution is stirred at 25° C. underargon for 17 hours, 10% hydrochloric acid solution is added to pH 3.5and the solid is filtered, washed with water, and dried at 40° C. invacuum to giveE-3-[2-n-butyl-1-{(2-chlorophenyl)-methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2propenoic acid.

Method B

(i) 2-n-butyl-1-(trimethylsilyl)ethoxymethylimidazole

Hexane-washed 80% sodium hydride (1.45 g, 0.0483 mol) indimethylformamide (80 mL) under argon was treated with a solution of2-n-butylimidazole (5.45 g, 0.0439 mol) in dimethylformamide (14 mL)dropwise at 25° C. and the reaction was stirred an additional hour. Then2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (7.68 g, 0.0461 mol)was added, the mixture was stirred for 18 hours at ambient temperatureand then partitioned between ice water and ethyl acetate. The washed,dried, concentrated organic solution was chromatographed over silica gelwith 1:1 hexane in ethyl acetate to yield 10.8 g (96%) of2-n-butyl-1-(trimethylsilyl)ethoxymethyl-imidazole.

(ii) 2-n-butyl-5-tributyltin-1-(trimethylsilyl)ethoxymethylimidazole

A solution of 2-n-butyl-1-SEM imidazole (prepared above) (6.37 g, 0.025mol) in ethyl ether (125 mL) was treated dropwise with n-butyl lithium(0.0255 mol, 10.2 mL of 2.5M in hexane) under argon at room temperature.After being stirred for an additional 45 minutes, tributyltin chloride(8.83 g, 7.4 mL, 0.026 mol) was added dropwise. The suspension wasstirred overnight, saturated ammonium chloride solution was added andthe ether layer was separated, washed with brine, dried over sodiumsulfate, concentrated and flash chromatographed over silica gel with 3:1hexane/ethyl acetate to provide 11.3 g (83%) of2-n-butyl-5-tributyltin-1-(trimethylsilyl)ethoxymethylimidazole.

(iii) ethyl (E andZ)-3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoate

To a solution ofn-butyl-5-tributyltin-1-(trimethylsilyl)ethoxymethylimidazole (0.0208mol) in m-xylene (150 mL) is added ethyl3-bromo-2-(5-methyl-2-furyl)methyl-2-propenoate (0.0233 mol), followedby tetrakis (triphenylphosphine) palladium (0) (0.416 mmol). Thereaction mixture is heated at 120° C. for 18 hours under argon. Thecooled mixture is washed with water, 10% ammonium hydroxide solution andbrine. The solution is treated with charcoal and sodium sulfate,filtered, concentrated and chromatographed over silica gel with 9:1hexane in ethyl acetate to give ethyl(Z)-3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoate.

(iv) ethyl (E andZ)-3-[3-n-butyl-1-t-butoxycarbonyl-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoate

A solution ethyl(E)-3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoate(1.24 g, 3.52 mmol) in ethanol (10 mL) is heated at 60° C. for 3.5 hourswith 5N hydrochloric acid solution (20 mL). The cooled reaction isbasified with 10% sodium hydroxide solution, extracted with ethylacetate, washed with water, dried and concentrated. The residue isdissolved in methanol (15 mL), triethylamine (1.5 mL, 10.6 mmol), anddi-tert-butyldicarbonate (2.3 g, 10.5 mmol) are added and the mixture isstirred for 18 hours at ambient temperature. The mixture is concentratedin vacuo and chromatographed over silica gel with 4:1 hexane/ethylacetate to give ethyl(Z)-3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoateas an oil. The (E)-isomer was prepared by the same procedure describedfor the (Z)-isomer.

(v) ethyl (E andZ)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoate

To a stirred solution of trifluoromethanesulfonic anhydride (387 mg,1.37 mmol) in methylene chloride (1 mL) held at -75° C. under argon isadded a solution of 2-chlorobenzyl alcohol (196 mg, 1.37 mmol) anddiisopropylethylamine (177 mg, 1.37 mmol) in methylene chloride (4 mL).After stirring for 20 minutes at -75° C., a solution of ethyl(Z)-3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoatein methylene chloride (2 mL) is added dropwise over 10 minutes and themixture was stirred overnight at 25° C. A solution of 5% sodiumbicarbonate solution is added with stirring and the layers areseparated, washed and dried. The reaction mixture is evaporated todryness, the residue triturated with 1:1 hexane/ethyl acetate, the solidfiltered off and the filtrate is concentrated and chromatographed oversilica gel with 7:3 hexane/ethyl acetate to provide the title compound.The title (E)-isomer is prepared by the same procedure described for the(Z) isomer.

(vi)(Z)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoicacid

The title compounds are prepared by basic hydrolysis of thecorresponding ethyl esters according to the procedure described inExample 6, Method A.

EXAMPLE 7(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl)}-1H-imidazol-5-yl]-2-(3-thienyl)methyl-2-butenoicAcid

(i) 2-n-butyl-1-(2-chlorophenyl)methyl-5-(α-hydroxy) ethyl-1H-imidazole

A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-carboxaldehyde (Example 1 (iii)) (1.1 g, 3.97 mmol) wasdissolved in dry tetrahydrofuran (15 mL), cooled to -78° C. under argonand a solution of methyl lithium (3.64 ml of 1.2M in diethyl ether, 4.57mmol) was added dropwise. The mixture was stirred for 1.5 hours,quenched with ammonium chloride solution, warmed to ambient temperatureand extracted with ethyl acetate. The washed, dried, concentratedproduct was flashed chromatographed over silica gel with ethyl acetateto provide 1.07 g (92%) of2-n-butyl-1-(2-chlorophenyl)methyl-5-(a-hydroxy) ethyl-1H-imidazole.

(ii) [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methylketone

A mixture of2-n-butyl-1-(2-chlorophenyl)methyl-5-(α-hydroxy)ethyl-1H-imidazole (1.07g, 3.65 mmol), activated manganese dioxide (6 g) and toluene (75 mL) washeated at 90° to 100° C. under a slight vacuum with a Dean Stark waterseparator for 17 hours. The inorganics were filtered, the concentratedfiltrate was applied to a flash silica gel column and the product waseluted with 3:7 hexane/ethyl acetate to give 0.628 g (59%) of[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methyl ketone.

(iii) methyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3-thienyl)methyl-2-butenoate

To absolute ethanol (3 mL) is added freshly cut sodium (55 mg). Thentrimethyl 3-(3-thienyl)-2-phosphonopropionate (2.16 mmol) and[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazole-5-yl]methyl ketone(0.628 g, 2.16 mmol) are added and the mixture is stirred at 70° C. for17 hours. The reaction is concentrated, partitioned between ethylacetate and water, and the organic layer was washed with water, dried,concentrated and chromatographed to afford the title compound.

(iv) (E) -3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3-thienyl)methyl-2-butenoic acid

The title compound is prepared according to Example 1 (Method A, iii) byusing methyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3-thienyl)methyl-2-butenoatein place of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate.

EXAMPLE 8(E)-3-[2-n-Butyl-1-{(2-chloro-6-fluoro-phenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)-methyl-2-propenoicAcid

(i) 2-n-butyl-1-(2-chloro-6-fluorophenyl)methyl-1H-imidazole

A solution of 2-n-butylimidazole (3.75 g, 0.03 mol) in drydimethylformamide (4 mL) was added to sodium hydride (0.95 g) indimethylformamide (18 mL). After the gas evolution subsided, the mixturewas stirred one hour under argon and 2-chloro-6-fluorobenzylchloride(5.5. g, 0.031 mol) in dimethylformamide (7 mL) was added to produce anexotherm. The mixture was stirred for 17 hours at ambient temperature,diluted with ice water and extracted with ethyl acetate. The washed,dried, concentrated organic layer provided 7.63 (94%) of the titlecompound whose NMR was consistent with the structure. This material wasused without further purification.

(ii)2-n-butyl-1-(2-chloro-6-fluorophenyl)-methyl-1H-imidazol-5-carboxaldehyde

The procedures of Example 1(ii-iii) were used. From 7.63 g of crude2-n-butyl-1-(2-chloro-6-fluorophenyl)-methyl-1H-imidazole andproportional amounts of other reagents was obtained 2.8 g of2-n-butyl-1-(2-chloro-6-fluorophenyl)methyl-5-hydroxymethyl-1H-imidazoleafter chromatography over silica gel with 3% of methanol in methylenechloride; mp 106°-108° C. (from ethyl acetate). This material wasoxidized with manganese dioxide and worked up as described above to give0.88 g (63%) of2-n-butyl-2-(2-chloro-6-fluorophenyl)methyl-1H-imidazol-5-carboxaldehyde;mp 88°-90° C. (from ethyl acetate).

(iii)(E)-3-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid

The procedure of Example 1, Method A is used.2-n-Butyl-1-(2-chloro-6-fluorophenyl)-methyl-1H-imidazole-5-carboxaldehyde,trimethyl 3-(2-thienyl)-2-phosphonopropionate, sodium hydride and glymeare held at 60° C. for 1 hour to give, after chromatography over silicagel with 50% of hexane in ethyl acetate, methyl(E)-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoateand corresponding cis or (Z)-isomer. The (E)-isomer is hydrolyzed toafford(E)-3-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid.

EXAMPLE 9(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)-2-propenoicAcid

A mixture of2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (2mmol), 2-thienylacetic acid (2.3 mmol), potassium carbonate (0.91 mmol),and acetic anhydride (1 mL) is heated gradually to 140° C. and held atthis temperature for 6 hours. The cooled reaction is diluted with waterand the solid is separated, triturated several times with ether, and thesolid is crystallized to give the title compound.

EXAMPLE 10(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-furyl)-2-propenoicAcid

This compound is prepared according to Example 9, using 2-furylaceticacid in place of 2-thienylacetic acid.

EXAMPLE 11(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-heptenoicAcid

(i) Ethyl 3-trifluoromethane-sulfonyloxy-2-heptenoate

Ethyl 3-ketoheptanoate (2.07 g, 12 mmol) was dissolved indimethylformamide (60 mL) under argon and sodium hydride (357 mg, 14.4mmol) was added. After 30 minutes at room temperature the solidN-phenyltrifluoro-methanesulfonamide (Tetra. Letters, (1983), 24, 979)(4.97 g, 13.8 mmol) was added. The reaction was stirred for 2 hours,diluted with ether/water and the usual workup gave after chromatographywith 5:95 ether/hexane 3.45 g (94%) of ethyl3-trifluoromethanesulfonyloxy-2-heptenoate.

(ii) ethyl (E)-3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-heptenoate

A solution of 2-n-butyl-5-tributyltin-1-(trimethylsilyl)ethoxymethylimidazole (Example 6, Method B (ii)) (3.63 mmol) and ethyl3-trifluoromethanesulfonyloxy-2-(2-thienyl)methyl-2-heptenoate (3.62mmol) in tetrahydrofuran (5 mL) is added to a mixture of lithiumchloride (11.1 mmol) and tetrakis(triphenylphosphine)palladium (0)(0.076 mmol) in tetrahydrofuran (10 mL). The reaction is heated toreflux under argon for 5 hours, cooled, diluted with ether and the etherlayer is washed with water, 10% ammonium hydroxide solution and brine.The extract is dried with sodium sulfate and concentrated. The productis chromatographed over silica gel with a gradient of hexane in ethylacetate to give the title compound.

(iii) ethyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-heptenoate

The procedure of Example 6, Method B (iv, v) is followed using ethyl(E)-3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2heptenoatein in place of ethyl (E)-3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-heptanoateto give the title compound.

(iv)(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-heptenoicacid

The ethyl ester, prepared above, is dissolved in ethanol and 10% sodiumhydroxide solution is added. An additional 1 ml of base is addedincrementally over several hours and the mixture is stirred overnight atroom temperature. The cooled reaction was acidified to pH 5 with dilutehydrochloric acid solution, extracted with methylene chloride and theresulting residue is triturated with ether/hexane to provide the titlecompound.

EXAMPLE 12(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-(3-thienyl)-2-butenoicAcid

(i) Ethyl 4-(3-thienyl)-3-trifluoromethanesulfonyloxy-2-butenoate

This compound was prepared according to Example 11(i) using ethyl4-(3-thienyl)-3-ketobutanoate in place of ethyl 3-ketoheptanoate.

(ii) ethyl(E)-3-[2-n-butyl-1-{(trimethylsilyl)-ethoxymethyl}-1H-imidazol-5-yl]-4-(3-thienyl)-2-butenoate

To a solution of 2-n-butyl-1-SEM-imidazole (Example 6, Method B(i))(5.32 mmol) in ethyl ether (16 mL) is added n-butyl lithium in hexane(6.5 mmol) at a slow rate. After an additional hour of stirring at 25°C., a solution of zinc chloride in ether (6.5 mL of 1.0M) is addedfollowed by tetrahydrofuran (15 mL). After an additional 75 minutes ofstirring, the zinc chloride imidazole adduct solution is transferredunder argon to a solution of ethyl4-(3-thienyl)-3-trifluoromethane-sulfonyloxybutenoate (6.41 mmol) andtetrakis(triphenylphosphine)palladium(0) (317 mg) in tetrahydrofuran (30mL). The reaction mixture is stirred at 25° C. for 20 hours and workedup as in Example 12 (ii) to provide ethyl(E)-3-[2-n-butyl-1-{trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-4-(3-thienyl)-2-butenoate.

(iii) ethyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-(3-thienyl)-2-butenoate

The title compound is prepared according to the procedure of Example 6,Method B(iv, v) using ethyl(E)-3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-4-(3-thienyl)-2-butenoatein place of ethyl(E)-3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoate.The title compound is an oil.

(iv)(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-(3-thienyl)-2-butenoicacid

The above ethyl ester (520 mg) is dissolved in ethanol (5 mL) and 5Nhydrochloric acid solution (40 mL), and the solution is slowly heated at100° C. with evaporation of the alcohol. After being heated at 100° C.for 6 hours, the reaction is cooled and the white precipitate iscollected, air-dried, and then triturated with ether/methanol to afford(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-(3-thienyl)-2-butenoicacid hydrochloride.

EXAMPLE 13(E)-4-[2-n-Butyl-1-{(2-chlorophenyl)-methyl}-1H-imidazol-5-yl]-3-(5-methyl-2-furyl)methyl-3-butenoicAcid

(i)(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenol

A solution of methyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoate(Example 6, Method A) (1.5 mmol) in dry tetrahydrofuran (10 mL) held at-78° C. under argon is treated dropwise with a solution of diisobutylaluminum hydride in toluene (3.30 mmol, 2.2 mL of 1.5M). The mixture isallowed to warm to ambient temperature and stirred an additional 17hours. Excess reducing agent is quenched with methanol and water, diluteacetic acid and methylene chloride are added, and the organic layer iswashed with sodium bicarbonate solution, dried and concentrated to givethe title compound.

(ii) ethyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenylcarbonate

To a solution of (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenol (6.86 mmol) inmethylene chloride (20 mL) and triethylamine (12.4 mmol) cooled to 0° C.under argon is added dropwise ethyl chloroformate (1.34 g, 1.18 ml, 12mmol). The reaction is then stirred at ambient temperature overnight.Ethyl acetate is added, the precipitate filtered and the concentratedfiltrate is flash chromatographed over silica gel with 3:7 hexane/ethylacetate to provide the title compound.

(iii) ethyl(E)-4-[2-n-butyl-1-{(2-chlorophenyl)methyl)-1H-imidazole-5-yl]-3-(5-methyl-2-furyl)methyl-3-butenoate

A solution of ethyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenylcarbonate (3.77 mmol) in tetrahydrofuran (12 mL) under an atmosphere ofcarbon monoxide is treated with triphenylphosphine (0.188 mmol) andpalladium diacetate and the mixture is heated at 40° C. for 21/2 hours.The concentrated reaction mixture is applied to a flash column of silicagel and eluted with 1:1 hexane/ethyl acetate to afford the titlecompound.

(iv)(E)-4-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]/-3-(5-methyl-2-furyl)methyl-3-butenoicacid

The compound is prepared according to the procedure of Example 1, MethodA(iii) using the above prepared ethyl ester in place of ethyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate.

EXAMPLE 14(E)-4-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-methyl-and -2,2-dimethyl-3-(2-thienyl)methyl-3-butenoic Acid

(i) ethyl(E)-4-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-methyl-3-(2-thienyl)methyl-3-butenoate

Lithium diisopropylamide (0.85 mmol, 1M in tetrahydrofuran) is cooled to-78° under argon and a solution of ethyl(E)-4-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-3-(2-thienyl)methyl)-3-butenoate(0.709 mmol), prepared as in Example 13 using methyl (E)3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate (Example 1), in tetrahydrofuran (5 mL) is added.After 10 minutes methyl iodide (0.71 mmol) is added. The mixture is thenstirred at room temperature overnight, diluted with 10% ammoniumchloride and extracted with ethyl acetate. The dried, concentratedproduct is chromatographed over silica gel with 6:4 hexane/ethyl acetateto give the title compound.

(ii)(E)-4-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-methyl-3-(2-thienyl)methyl-3-butenoicacid

A solution of the above prepared ethyl ester in ethanol is heated toreflux with 10% sodium hydroxide solution for 2 hours. The ethanol isevaporated, water is added and the aqueous layer is extracted withether. The water layer is acidified to pH 1 with dilute hydrochloricacid solution, extracted with ethyl acetate, dried and concentrated to asolid. Trituration with ether provides the hydrochloride salt of thetitle compound.

(iii)(E)-4-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2,2-dimethyl-3-(2-thienyl)methyl-3-butenoicacid

This compound is prepared according to the procedure of Example 14(i,ii) using two equivalents of methyl iodide.

EXAMPLE 15(E)-4-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-3-(2-thienyl)methyl-3-butenoicAcid

This compound is prepared according to the procedure of Example 14(i,ii) using less than one equivalent of 2-chloromethylthiophene in placeof methyl iodide.

EXAMPLE 16(E)-4-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-3-(2-thienyl)methyl-3-butenoicAcid

This compound is prepared according to Example 14(i,ii) but using lessthan one equivalent of benzyl bromide at higher solvent dilution.

EXAMPLE 17(E,E)-5-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-(2-thienyl)methyl-2,4-pentadienoicAcid

(i)(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenol

To a solution of methyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate,prepared in Example 1, ((2.60 g. 6.06 mmol) in 35 mL of tetrahydrofuranat -78° C. under argon was added a solution of diisobutylaluminumhydride (1.5M, 8.9 mL, 13.3 mmol). After the addition was complete, thereaction mixture was allowed to warm to room temperature, with stirringbeing continued for one hour. The reaction was worked up by the slowaddition of methanol, followed by the addition of glacial acetic acid,then four drops of 10% aqueous hydrochloric acid solution. Water (10 mL)was added and the reaction mixture was stirred at room temperatureovernight. The product was extracted with ethyl acetate (3×75 mL) after40 mL of water had been added to the mixture. The combined extracts weredried with anhydrous magnesium sulfate and the solvents were removed invacuo. The residue was triturated with diethyl ether. The resultingsolid was filtered to give 1.72 g (71%) of product; mp 114°-115° C.

(ii)(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(2-thienyl)-methyl-2-propionaldehyde

To a suspension of 8.0 g of manganese dioxide in 80 mL of benzene wasadded(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenol(1.61 g, 4.02 mmol). The reaction was stirred vigorously for 0.5 hours.The solids were filtered and washed with ethyl acetate. The filtrate wasconcentrated to near-dryness and then the residue was triturated withhexane. The resulting solid was filtered to give 0.669 g of product; mp163.5°-164.6° C.

The filter cake was heated with ethyl acetate for 10 minutes and thesolids were filtered. The filtrate was cooled in ice/water and theresulting solid was filtered to give 0.712 g of additional product; mp163.5°-164.5° C.

(iii) ethyl(E,E)5-[2-n-butyl-1-{(2-chlorophenyl)methyl)-1H-imidazol-5-yl]-4-(2-thienyl)-methyl-2,4-pentadienoate

To a suspension of(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propionaldehydein 8 mL of toluene was added (carbethoxymethyl)triphenylphosphorane. Thereaction was heated overnight at 40° C. After cooling to roomtemperature, the solids were filtered to give 0.181 mg of crude product.Chromatography on silica gel eluting with hexane/ethyl acetate (6:4)gave 0.2345 g (50%) of the title compound as an oil.

(iv)(E,E)-5-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-(2-thienyl)methyl-2,4-pentadienoicacid

The title compound was prepared according to the procedure of Example 1(iv), Method A(c) using the above prepared ethyl ester; hydrochloricacid salt, mp 191°-192.5° C.

Alternately, the sodium salt of the acid is isolated directly from thereaction mixture, prior to neutralization. The crude basic reactionsolution is applied to a reverse-phase flash column equilibrated withwater. The inorganics are washed from the column with water (3 voidvolumes) and then the product is eluted with a 50:50 mixture ofacetonitrile in water. The acetonitrile is removed in vacuo and then thedesired sodium salt is obtained after lyophilization.

EXAMPLE 18(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid, 2-(N,N-Diethylamino)-2-oxoethyl Ester

A solution of(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid (Example 1) (5 mmol) in dry dimethylformamide (10 mL) was treatedwith 2-chloro-N,N-diethyl-acetamide (5.51 mmol) followed by powderedpotassium carbonate. This mixture was heated at 70° C. for 7 hours,diluted with water and extracted with ethyl acetate. The water-washed,dried, concentrated product solidifies and after trituration withether/hexane affords the title ester; mp 139°-140° C.

EXAMPLE 19(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl-4-hydroxymethyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

(i)2-n-butyl-1-(2-chlorophenyl)methyl-4-(t-butyldimethylsilyloxy)-methyl-1H-imidazol-5-carboxaldehyde

A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-4,5-bis(hydroxy)methyl-1H-imidazole (Example 1 (ii)) (310 mg, 1 mmol) inmethylene chloride (5 mL) was treated with 4-dimethylaminopyridine (5.2mg), triethylamine (1.5 mmol) and t-butyl dimethylsilyl chloride (192mg, 1.24 mmol). The mixture was stirred at 25° C. for 20 hours, dilutedwith water and the organic layer was washed well with water, dried,concentrated and chromatographed over silica gel with an ethylacetate/methanol gradient to afford 127 mg (24%) of the bis(4,5-t-butyldimethylsilyl) ether and 252 mg (59%) of2-n-butyl-1-(2-chlorophenyl)methyl-4-t-butyldimethysilyloxymethyl-5-hydroxymethyl-1H-imidazole.This monoether (252 mg) was oxidized to the 5-carbox-aldehyde usingmanganese dioxide as described in Example 1 (iii) to provide 170 mg of2-n-butyl-1-(2-chlorophenyl)-methyl-4-(t-butyldimethylsilyloxy)methyl-1H-imidazol-5-carboxaldehydeas an oil.

(ii) ethyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl]-4-(t-butyldimethyl-silyloxy)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate

In tetrahydrofuran (80 mL) is added n-butyl lithium (15.5 mmol inhexane) and at -78° C. under argon is then added diisopropylamine (2.4mL, 17.1 mmol). Methyl 3-(2thienyl)propanoate (15.3 mmol) is added neatover 5-6 minutes, and the mixture was stirred an additional 30 minutesat -78° C. A solution of2-n-butyl-1-(2-chlorophenylmethyl-4-(t-butyldimethylsilyloxy)methyl-1H-imidazol-5-carboxaldehyde (10.2 mmol) in tetrahydrofuran (10 mL) is added viacannula, and the reaction mixture is stirred for 15 minutes. Thereaction is partitioned between saturated ammonium chloride and ether,and the ether layer is washed with water, dried and concentrated to givecrude product. This is chromatographed over silica gel with 20-50% ofethyl acetate in hexane to afford a mixture of isomeric β-hydroxyesterproducts. A solution of this mixture (8.54 mmol) in methylene chloride(100 mL) is treated with 4-dimethylaminopyridine (3 mmol) followed byacetic anhydride (84 mmol), and the solution is stirred at roomtemperature for 5 hours. The reaction is poured into water, stirred for20 minutes and the product is extracted into ether. The ether extractsare washed with dilute hydrochloric acid solution, water, sodiumbicarbonate solution and brine. The dried, concentrated mixture ofβ-acetoxyester products is used directly in the elimination reaction. Toa solution of the β-acetoxyester product (4.5 mmol) in toluene (60 mL)is added of 1,8-diazabicyclo[ 5.4.0]undec-7-ene (DBU) (10.9 mmol), andthe mixture is heated at 90° C. for 24 hours. The reaction isconcentrated to 10 mL, diluted with ether and flash filtered through a14×3 cm plug of silica gel with ether rinses to afford the crudeolefinic product. Chromatography over silica gel with an ethyl acetatein hexane gradient gives homogeneous ethyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl]-4-t-butyldimethyl-silyloxymethyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate.The elimination of the acetate with DBU produces predominantly the trans(E)isomer.

(iii)(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl-4-hydroxymethyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid

A solution of ethyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)-4-t-butyldimethylsilyloxymethyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate(0.287 mmol) in absolute ethanol (3 mL) is treated portionwise at 6 hourintervals with 10% sodium hydroxide solution (3×1 mL). After beingstirred overnight at 25° C., the reaction is heated to 50° C. for 4hours, then concentrated in vacuo. The residual product is taken up inwater, acidified to pH 5-6 and extracted with methylene chloride. Theisolated, dried, concentrated product is triturated with methanol/etherto provide the title compound.

EXAMPLE 20(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-pyridyl)methyl-2-propenoicAcid

(i) methyl3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-(4-pyridyl)methylpropanoate

To a solution of diisopropylamine (3.58 mL, 25.6 mmol) in drytetrahydrofuran (50 mL) held at -78° C. under argon was added n-butyllithium (10.2 mL, 25.6 mmol of 2.5M in toluene), and the mixture wasstirred for 10 minutes. Then, methyl 3-(4-pyridyl)propanoate (4.22 g,25.6 mmol) (prepared by reaction of 4-pyridine carboxaldehyde withtrimethyl phosphonoacetate in the presence of sodium hydride in ethyleneglycol dimethyl ether, followed by catalytic hydrogenation of the doublebond with 10% palladium on carbon at 3 atmosphere of hydrogen in anethyl acetate solution (98%) to provide the saturated ester) was addedin tetrahydrofuran (40 mL) and this mixture was stirred for 30 minutesat -78° C. A solution of2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (5.9 g,21.3 mmol) in tetrahydrofuran (10 mL) was added and stirring wascontinued for 30 minutes at -78° C. The reaction was partitioned betweensaturated ammonium chloride solution and ether, the organic extract waswashed with brine, dried over magnesium sulfate, concentrated and flashchromatographed over silica gel with 5% methanol in ethyl acetate toprovide 3.32 g (30%) of methyl3-[2-n-butyl-1-(2-chlorophenyl)-methyl-1H-imidazol-5-yl]-3-hydroxy-2-(4-pyridyl)methylpropanoate.TLC on silica gel with 5% methanol in ethyl acetate showed a homogenousproduct with an R_(f) of 0.79.

(ii) methyl3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(4-pyridyl)propanoate

A solution of methyl3-[2-n-butyl-1-(2-chlorophenyl)-methyl-1H-imidazol-5-yl]-3-hydroxy-2-(4-pyridyl)-methylpropanoate(3.32 g, 7.5 mmol)methylene chloride (50 mL), 4-dimethylaminopyridine(150 mg, 1.3 mmol) and acetic anhydride (7.1 mL, 75 mmol) was stirred atambient temperature for 18 hours. Water (5 mL) was added, the mixturewas stirred for 2 hours and then diluted with methylene chloride and 5%sodium bicarbonate solution. The organic phase was washed with 5% sodiumbicarbonate solution and brine, dried and concentrated to give 4 g ofthe crude title compound. TLC on silica gel with 5% methanol ethylacetate showed essentially one spot material with an R_(f) of 0.86. Nostarting material was detected. This material was not purified further.

(iii) methyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl)}-1H-imidazol-5-yl]-2-(4-pyridyl)methyl-2-propenoate

A mixture of methyl3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(4-pyridyl)propenoate (7.5 mmol), toluene (50 mL) and1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) (3.4 mL, 22.5 mmol) was heatedat 90° C. for 18 hours under argon. The cooled mixture was diluted withether, and washed with brine, dried and concentrated to 3.1 g (97%) ofthe title compound. NMR showed that the trans or E isomer was theprimary product.

(iv)(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-pyridyl)-methyl-2-propenoicacid

A solution of methyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-pyridyl)methyl-2-propenoate (3.1 g, 7.3 mmol) in ethanol (16 mL) was treatedwith 10% sodium hydroxide solution and the mixture was stirred for 18hours at 25° C. The solution was concentrated in vacuum, water wasadded, the pH was adjusted to 6.5 and the resulting solid was filtered,washed with water and crystallized from methanol/ether to afford 0.48 gof(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-pyridyl)methyl-2-propenoicacid; mp 178°-182° C. (d).

EXAMPLES 21-26

In Table II are listed other examples of alkenoic acids prepared by themethods described in Example 20 (i-iv). The starting materials andproducts are shown in Table II.

                                      TABLE II                                    __________________________________________________________________________     ##STR11##                                                                    Ex-                                                                           am-                                                                           ple                                                                              Starting Materials                     R.sup.3                                                                         Product (R.sup.5).sup.a                                                                    mp                   __________________________________________________________________________    21                                                                                ##STR12##                                                                                          ##STR13##        H                                                                                ##STR14##   184-185°                                                               C.                   22 (II)                                                                                                ##STR15##        H                                                                                ##STR16##   156-160°                                                               C. (d)               23 (II)                                                                                                ##STR17##        H                                                                                ##STR18##   161-164°                                                               C.                   24 (II)                                                                                                ##STR19##        H                                                                                ##STR20##   169-170°                                                               C.                   25 (II)                                                                                                ##STR21##        H                                                                                ##STR22##   173.5- 175.degree                                                             . C..sup.b           26                                                                                ##STR23##                                                                                          ##STR24##        Cl                                                                               ##STR25##   175- 176°                                                              C..sup.b             __________________________________________________________________________     .sup.a Product prepared by the 4 step synthetic route described in Exampl     20. The penultimate olefinic ester is purified, if necessary, by              chromatography over silica gel with ethyl acetate/hexanes or                  methanol/ethyl acetate mixtures.                                              .sup.b Hydrochloride salt.                                               

EXAMPLE 27

By the procedure of Example 20 (i-iv) using in place of methyl3-(4-pyridyl)propanoate, the following:

methyl 3-(4-thiazolyl) propanoate,

methyl 3-(1,2,3,4-tetrazol-5-yl)propanoate, and

methyl 3-(1-tosylpyrazol-3-yl) propanoate;

the products are:

3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-thiazolyl)methyl-2-propenoicacid,

3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(1,2,3,4-tetrazol-5-yl)methyl-2-propenoicacid, and

3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3-pyrazolyl)methyl-2-propenoicacid.

EXAMPLE 28(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-4-fluoro-1H-imidazol-5-yl]-2-(2-thienyl]methyl-2-propenoicAcid

Anhydrous hydrochloric acid (20.5 g, 0.562 mol) bubbled into a stirredsolution of valeronitrile (31.8 g, 40.0 mL, 0.383 mol) in methanol(13.47 g, 17 mL, 0.421 mol) which was cooled by a ice/acetone bath. Thereaction was capped tightly and then stored at 10° C. overnight. To thissolid mixture at 10° C. under argon was added 100 mL of t-butyl methylether. Once a free-flowing crystalline mixture had formed, the solid wascollected and washed with 400 mL of t-butyl methyl ether. The solid wasimmediately placed in a vacuum desicator over phosphoric anhydride andsodium hydroxide to give 55.50 g (96%) of valeramidine methyl etherhydrochloride; mp 103°-105° C.

The procedure of W. Lwosski, Synthesis, 263 (1971) was followed. To amixture of valeramidine methyl ether hydrochloride (37.91 g, 0.25 mol)and 50% aqueous cyanamide (13.53 g, 25 mL, 0.322 mol) cooled in an icebath was added portionwise anhydrous disodium phosphate (12.01 g, 0.0846mol). After the addition was complete, the ice bath was removed and anoil and solid began to come out of solution. After stirring for anadditional 30 minutes, the oil was decanted from the solid. The solidwas partitioned between water and diethyl ether and the oil was alsodissolved in diethyl ether. The combined organic extracts were washedwith saturated sodium chloride solution and then dried with anhydroussodium sulfate. The solvent was removed in vacuo to give 33.06 g (94%)of valercyanamidine methyl ether.

To a solution of the amidine methyl ether prepared above (33.06 g, 0.236mol) in 225 mL of absolute ethanol was added in one portion2-chlorobenzylamine (33.39 g, 0.236 mol). The reaction was stirred atroom temerpature for 2 hours and then the solvent was removed in vacuoto give 55.4 g (94%) of a solid, whose NMR indicated the absence of themethyl ether functionality.

The secondary amine was alkylated using the following procedure. Amixture of the product prepared above (35.0 g, 0.14 mol) and potassiumcarbonate (67.72 g, 0.49 mol) in 200 mL of dimethylformamide was stirredunder argon at 60° C. for 15 minutes. To this mixture was added over 10minutes ethyl bromoacetate (24.56 g, 0.143 mol). After the addition wascomplete, the reaction temperature was raised to 75°-80° C. After 30minutes, the reaction mixture was filtered. The filtrate wasconcentrated in vacuo. The residue was partitioned between ethyl acetateand water. The organic extract was washed with water (5×) and saturatedsodium chloride solution. The organic extract was dried with anhydroussodium sulfate and then the solvent was removed in vacuo. The crudeproduct was chromatographed on silica gel eluting with ethyl acetate inhexane to give 37.15 g (79%) of an oil.

2-n-Butyl-1-{(2-chlorophenyl)methyl}-4-amino-5-carboethoxyimidazole wasprepared by the following procedure. Sodium metal (2.54 g, 0.110 g-atom)was dissolved in absolute ethanol under argon. To this solution wasadded a solution of the above-prepared product (37.07 g, 0.110 mol) in175 mL of absolute ethanol over a 15 minute period. After the additionwas complete the reaction mixture was stirred for one hour at roomtemperature. The resulting solid was collected, washed with water, andair-dried to give 25 g of product; mp 120°-121° C.

The 4-amino product was fluorinated using the procedure of K. L. Kirkand L. J. Cohen, JACS, 95 (14), 4619 (1973). Fluoroboric acid (48%, 150mL) was added to2-n-butyl-1-{(2-chlorophenyl)methyl}-4-amino-5-carboethoxyimidazole(10.75 g, 0.032 mol) in a quartz flask. The resulting solid mass wassonicated and stirred vigorously to form a suspension. This suspensionwas cooled to 0° C. and then sodium nitrite (2.80 g, 0.0406 mol) in 5 mLof water was added slowly. The ice bath was removed and then thereaction mixture was irradiated for 20 hours with a 450-watt mercuryvapor lamp placed in a quartz immersion well, cooled by circulatingwater. The reaction mixture was cooled to -20° C. and the pH wasadjusted to 6.4 with 50% aqueous sodium hydroxide. The product wasextracted into ethyl acetate (3×) and the combined extracts were washedwith water and saturated sodium chloride solution. The organic extractwas dried with anhydrous sodium sulfate and concentrated to give 8.43 gof a crude product, which was chromatographed on silica gel eluting withchloroform to give 4.31 g of2-n-butyl-1-{(2-chlorophenyl)methyl}-4-fluoro-5-carboethoxyimidazole.

This carboethoxy compound was converted to the corresponding 5-formylderivative following the procedure of Example 17 (i and ii).

2-n-Butyl-1-{(2-chlorphenyl)methyl}-4-fluoro-5-formylimidazole wasconverted toE-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-4-fluoro-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid following the procedure of Example 20 (i-iv) replacing methyl3-(4-pyridyl)propanoate with methyl 3-(2-thienyl)-propanoate; mp126°-127° C.

EXAMPLE 29(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-4-bromo-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

By the procedure of Example 28 using the corresponding 4-bromo startingmaterial (prepared by the method described in U.S. Pat. No. 4,340,598),the title compound is prepared.

EXAMPLE 30(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-4-trifluoromethyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

Using2-n-butyl-1-(2-chlorophenyl)methyl-4-trifluoroethyl-1H-imidazol-5-carboxaldehyde(prepared by treating the corresponding 4-bromo compound withtrifluoromethyl iodide and copper) in the procedure of Example 20 givesthe title compound.

EXAMPLE 31

By the procedure of Example 1, using in place of 2-chlorobenzyl bromide,the following:

2-methylbenzyl bromide,

4-methoxybenzyl bromide, and

4-phenylbenzyl bromide;

and using the phosphonopropionate of Example 1, (MeO)₂ P(O)CH(CH₂-2-thienyl)COOMe, the following products are obtained:

(E)-3-[2-n-butyl-1-{(2-methylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid,

(E)-3-[2-n-butyl-1-{(4-methoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, and

(E)-3-[2-n-butyl-1-{(4-phenylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid.

EXAMPLE 32

The following methyl ester of a propenoate are prepared as in Example31:

methyl(E)-3-[2-n-butyl-1-[(4-methoxyphenyl)-methyl]-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate.

This is treated with boron tribromide in methylene chloride at roomtemperature for six hours and then the reaction mixture is condensed andtreated with a mixture of ethyl acetate and water. The washed ethylacetate layer gives on evaporation:

(E)-3-[2-n-butyl-1-[(4-hydroxyphenyl)methyl]-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid.

EXAMPLE 33(E)-3-[2-(1-Butenyl)-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

A mixture of2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde andN-bromosuccinimide in carbon tetrachloride was irradiated to give the2-(1-bromobutyl)imidazole which was dehydrobrominated by treating1,8-diazabicyclo[4.5.0]undec-1-ene in tetrahydrofuran to give2-(1-butenyl)-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde.

The above prepared intermediate and the 3-(2thienyl)propenoate ofExample 1 in the procedure of Example 1 was used to give the titlecompound; mp 224°-226° C.

EXAMPLE 34 (E)-3-[2-Phenyl-1-{(2-chlorophenyl)methyl}-1H,imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic Acid

By the procedure of Example 1(ii) Method 2, using benzamidine methylether in place of valeramidine methyl ether,2-phenyl-5-hydroxymethylimidazole is prepared and converted to2-phenyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole. The5-hydroxymethyl group is oxidized using manganese dioxide by theprocedure of Example 1 (iii). The resulting2-phenyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde is usedin the procedure of Example 21 with methyl 3-(2-thienyl)propanoate togive the title compound.

EXAMPLE 35

By the procedure of Example 34 using the following amidine methylethers:

C₁₀ H₂₁ C═NH(OCH₃) and

C₂ H₅ C═NH(OCH₃);

the following products are obtained:

(E)-3-[2-decyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid and

(E)-3-[2-ethyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid.

EXAMPLE 36(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-4-formyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound is prepared by dilute hydrochloric acid hydrolysis ofthe 4-t-butyldimethylsilyloxy group of ethyl3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-4-(t-butyldimethyl-silyloxy)methyl]-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate,prepared as in Example 20 (ii), followed by manganese dioxide oxidationof the 4-hydroxymethyl group to the carboxaldehyde.

EXAMPLE 373-[1-(2-Adamantyl)ethyl)-2-n-butyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

A mixture of 2-(1-adamantyl)ethanol (10.7 g and diisopropylethylamine(11 ml) in methylene chloride (70 ml) was added to triflic anhydride(16.75 g) in methylene chloride (70 ml) at -78° C. under argon. Afterstirring the mixture at -78° C. for 45 minutes, 1-acetyl-2-n-butyl-5-(acetoxymethyl)imidazole in methylene chloride (50 ml) was added andthe mixture was allowed to stand at room temperature for 4 days, thenconcentrated and heated on a steam bath with 10% sodium hydroxide (250ml), diluted with 300 ml of water, extracted with methylene chloride,dried, filtered and concentrated to give an oil. Chromatography (silicagel) in methanol-chloroform gives5-acetoxymethyl-1-[2-(1-adamantyl)ethyl]-2-n-butylimidazole.

The above prepared compound (5.4 g) was stirred at room temperature withpotassium hydroxide (5.2 g) in ethanol (200 ml) for one hour. Themixture was concentrated, poured into water, stirred and filtered togive 1-[2-(1-adamantyl)ethyl]-2-n-butyl-5-hydroxymethyl-imidazole. Thehydroxymethyl group was oxidized by refluxing the imidazole compound(51.1 g) with manganese dioxide (20.3 g) in toluene (200 ml) to give1-[2-(1-adamantyl)ethyl]-2-n-butyl-imidazol-5-carboxaldehyde.

Diisopropylamine (0.563 g) was covered with 5 ml of tetrahydrofuran and2 ml of 2.5M n-butyl lithium in hexane was added at -78° C. The mixturewas stirred for 15 minutes, then methyl 3-(2-thienyl) propenoate (0.89g) in 3 ml of tetrahydrofuran was added. After 20 minutes, 1.04 g of1-[2-(1-adamantyl)ethyl]-2-n-butyl-imidazol-5-carbox-aldehyde in 3 ml oftetrahydrofuran was added and the mixture was stirred for 30 minutes at-78° C. The mixture was poured into 40 ml of saturated ammonium chloridein water, extracted with ether, dried over magnesium sulfate, filtered,concentrated and chromatographed on silica gel eluting with 70% ethylacetate and 30% hexane to give methyl3-[1-(2-(1-adamantyl)ethyl)-2-n-butyl-1H-imidazol-5-yl]-3-hydroxy-2-(2-thienylmethyl)propanoate.To 1.27 g of this compound in methylene chloride (25 ml) was added4-dimethylaminopyridine (1.25 g), then acetic anhydride (2.75 g) wasadded dropwise. The mixture was stirred for one hour, then poured intowater and worked up to give3-acetoxy-3-[1-(2-(1-adamantyl)ethyl)-2-n-butyl-1H-imidazol-5yl]-2-(2-thienylmethyl)propanoate.

The above prepared compound (1.2 g) was heated with1,8-diazabicyclo[5,4,0]undec-7-ene (1 ml) in toluene (20 ml) at 80° C.with stirring for one hour. The mixture was concentrated, then stirredwith ether. The ether layer was decanted and dried, filtered,concentrated and chromatographed to give methyl3-[1-(2-(1-adamantyl)ethyl)-2-n-butyl-1H-imidazol-5-yl]-2-(2-thienylmethyl)-2-propenoate.

This ester (0.63 g) was hydrolyzed in ethanol (10 ml) using potassiumhydroxide (0.18 g) to give the title compound; 218°-220° C.

EXAMPLE 38(E)-3-[2-n-Butyl-1-[(2-chlorophenyl)methyl]-4-carboxy-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

(E)-3-[2-n-Butyl-1-[(2-chlorophenyl)methyl]-4-hydroxymethyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid, prepared as in Example 19, is esterified with 4-methoxy-benzylalcohol to give the p-methoxybenzyl propenoate. The 4-hydroxymethylgroup in acetone is oxidized using an acidic aqueous solution containingchromic acid (Jones' reagent) and the ester is hydrolyzed using 10%sodium hydroxide to give the title compound.

EXAMPLE 39(E)-3-[2-n-Butyl-1-[(2-chlorophenyl)methyl]-4-carbamoyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

4-Methoxybenzyl(E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-4-carboxy-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate,prepared as in Example 38, is treated with oxalyl chloride in methylenechloride at 0° C. to give the acid halide which is treated with ammoniumhydroxide and the ester is hydrolyzed to give the title compound.

EXAMPLE 40(E)-3-[2-n-Butyl-1-[(2-chlorophenyl)methyl]-4-dimethylcarbamoyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

Treating the 4-chloroformyl imidazole, prepared as in EXAMPLE 39, withdimethylamine instead of ammonium hydroxide gives the title compound.

EXAMPLE 41(E)-3-[2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

(i) By the procedure of Example 1 [(ii) Method 2, (iii) and (iv) MethodB] using 4-carbomethoxybenzyl alcohol in place of 2-chlorobenzylalcohol, the title compound was prepared; mp 250°-253° C.

(ii) Preparation of Monomethanesulfonate

The title compound, 3600 g, was added to 2-propanol (54 L) in a20-gallon, glass-lined reactor. The stirred suspension was cooled toapproximately 8° C. Methanesulfonic acid (2448 g) was added rapidly tothe vigorously stirred suspension. The starting material dissolvedquickly to give a clear solution within two minutes. A slight exothermto approximately 11° C. was observed. A fine, white solid began toprecipitate from the solution within an additional three minutes. Thesuspension was stirred at a temperature of 3° C. for 5.5 hours and thesolid was collected by centrifugation. After washing with 10 L of2-propanol, the product was dried under vacuum at 45° C. to a constantweight of 4.21 kg (94% yield, uncorrected for assay).

The crude product (4.20 kg) was charged as a solid to 12.6 L of stirred,glacial acetic acid in a 10-gallon, glass-lined reactor. The slurry washeated to 80° C., giving a homogeneous solution. The solution wasfiltered warm through an in-line filter, and the reactor and filterlines were washed with 4.2 L of additional acetic acid. The combinedacetic acid solutions were stirred with slow cooling to 25° C. in aseparate 10-gallon, glass-lined reactor. Precipitation of a solid beganto occur at about 45° C. After 2.5 hours the suspension was diluted with42 L of ethyl acetate, added in two equal portions with a one hourinterval between additions. The suspension was stirred for an additional18 hours to allow complete precipitation. The solid product wascollected by centrifugation and washed with 10 L of ethyl acetate. Afterdrying to a constant weight under vacuum at 40° C., a recovery of 3.80kg of product; mp 251°-252° C. (90.4%, uncorrected for assay) wasobtained.

EXAMPLE 42(E)-3-[2-n-Butyl-1-{(4-carboxy-2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

A suspension of 2-butylimidazol-5-aldehyde (16,92 g, 0.111 mol, preparedby manganese dioxide oxidation of the alcohol, prepared in Example1,Method 2), chloromethyl pivalate (21.77 g, 0.145 mol), and potassiumcarbonate (20.07 g, 0.145 mol) in 200 ml of dimethylformamide wasstirred at ambient temperature under argon for four days. The solidswere removed by filtration and washed with ether. The combined filtrateswere partitioned between diethyl ether and water. The ether phase waswashed successively with water and brine, dried over magnesium sulfateand concentrated under vaccum to give 23.6 g of2-n-butyl-1-pivalyloxymethylimidazole-5-aldehyde.

A mixture of ethyl 4-bromomethyl-3-chlorobenzoate (5.28 g, 0.020 mol,U.S. Pat. No. 4,837,333) and2-n-butyl-1-pivaloyloxymethyl-imidazole-5-aldehyde (4.45 g, 0.0167 mol)was heated at 100° C. under argon for 18 hours. Repeated triturationwith ether gave 6.38 g of a crystalline salt. A suspension of this saltin 100 ml of ethyl acetate was stirred for 0.5 hours with 100 ml of 5%aqueous sodium carbonate. The layers were separated, the aqueous layerwashed with ethyl acetate, and the combined organic layers washed withwater, dried over magnesium sulfate and concentrated to give an oil.Chromatography of this oil over silica eluting gel with ethylacetate/hexane (1:1) gave 1.02 g of2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehyde.

Ethyl 2-carboxy-3-(2-thienyl)propionate (14 g, 0.061 mol) was preparedby stirring a solution of diethyl 2-thienylmalonate (16.8 g, 0.0655 mol)and potassium hydroxide (4.41 g, 0.0786 mol) in 200 ml of ethanol underargon at room temperature for 12 days and then purifying by removing thesolvent under vacuum, dissolving the reside in water, washing theaqueous layer with aqueous hydrochloric acid and with diethyl ether.

A solution of this half-acid, half-ester (1.05 g, 4.62 mmol) in 5 ml oftoluene was added to a refluxing solution of2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]-imidazole-5-aldehyde(1.03 g, 3.08 mmol) and piperidine (0.26 g, 3.08 mmol) in 60 ml oftoluene. Twice, at 1 hour intervals, an additional 1 g of the half-acid,half-ester was added, and the solution was then refluxed for 17 hours.Evaporation of the toluene and chromatography of the residue over silicagel using 2:3 ethyl acetate-hexane for elution gave 0.39 g of thediester of the title product. This was hydrolyzed in 2:1 ethanol-waterwith 5 equivalents of potassium hydroxide for 18 hours and worked up inthe usual manner to give 0.260 g of final product; mp 234°-236° C. TheNMR of this product was in accord with its structure.

EXAMPLE 43(E)-3-[2-n-Butyl-1-{(4-sulfonamidophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The procedure of Example 42 is followed using4-bromomethylbenzenesulfonamide (Braselton, et al., Anal. Chem., 48,1386 (1976)) in place of methyl 4-bromomethyl-3-chlorobenzoate to givethe title compound.

EXAMPLE 44(E)-3-[2-n-Butyl-1-{(4-carboxy-2-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The procedure of Example 42 was followed using methyl4-bromomethyl-3-nitrobenzoate (prepared from 4-methyl-3-nitrobenzoicacid by esterification with gaseous hydrochloric acid-methanol followedby methyl bromination with N-bromosuccinimide) to give the titlecompound; mp 163° C.

EXAMPLE 45(E)-3-[2-n-Butyl-1-{(4-carboxy-3-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The procedure of Example 42 was followed using ethyl4-bromomethyl-2-chlorobenzoate (U.S. Pat. No. 4,837,333) in place ofethyl 4-bromomethyl-3-chloro-benzoate to give the title compound;245°-246° C.

EXAMPLE 46(E)-3-[1-{(2-Chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

(i) 5-carboxymethyl-1-(2-chlorophenyl)methyl-2-thio-1H-imidazole

A solution of 2-chlorobenzylamine (14.2 g, 0.1 mol) and triethylamine(13.9 ml, 0.1 mol), in dimethylformamide (100 ml) was treated withmethyl chloroacetate (10.9 g, 0.1 mol), and the mixture was heated at50° C. for 3.5 hours. The cooled reaction mixture was diluted withether, the solids filtered and the concentrated filtrate was flashchromatographed over silica gel with 6:5 hexane in ethyl acetate toprovide 15.3 g (71%) of homogeneous methyl2-[N-(2-chlorophenyl)methyl]aminoacetate. This product (15.2 g, 0.071mol) in mixed xylenes (100 ml) was treated with 98% formic acid (2.74ml), 0.0711 mol) and the mixture was refluxed from 2.5 hours with aDean-Stark water separator. Evaporation gave 17.1 g (99%) of methyl2-[N-(2-chlorophenyl) methyl-N-formyl) aminoacetate. This formylatedproduct (17.0 g, 0.071 mol) was dissolved in methyl formate (13.3 ml,0.216 mol) and added dropwise to a sodium methoxide mixture prepared byadding sodium metal (1.79 g, 0.0778 g-atom) to tetrahydrofuran (325 ml)followed by slow addition of methanol (3.15 ml, 0.0778 mol). Thecombined mixture was stirred at room temperature for 18 hours, thenevaporated to dryness. This crude product was dissolved in 50% aqueousmethanol (200 ml), treated with charcoal, filtered and the solution wascooled in ice. Concentrated hydrochloric acid followed by a solution ofpotassium thiocyanate (8.6 g, 0.0885 mol) in water (20 ml). The mixturewas heated in an oil bath held at 90° C. for 2.5 hours, then cooled to10° C. The precipitated solid was filtered, washed with coldehtanol-water and dried at 60° C. to provide 14.7 g (74%) of5-carboxymethyl-1-(2-chlorophenyl)methyl-2-thio-1H-imidazole; mp 72°-74°C.

(ii) 1-(2-chlorophenyl)methyl-5-carboxymethyl-2-propylthio-1H-imidazole

A mixture of5-carboxymethyl-1-(2-chlorophenyl)methyl-2-thio-1H-imidazole (2 g, 7.08mmol, ethyl acetate (20 ml), 5% sodium carbonate solution (40 ml) andpropyl bromide (4 ml, 44 mmol) was heated at 60° C. for 18 hours. Theorganic layer was separated, dried over magnesium sulfate andconcentrated to 2.23 g of crude product. Trituration with ether provided1.63 g (71%) of5-carboxymethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole; mp68°-71° C. (from hexane).

(iii)E-3-[1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid

A solution of5-carboxymethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole (3.74g, 11.5 mmol) in dry tetrahydrofuran (50 ml) was cooled to -78° C. underargon, and a solution of diisobutyl alumninum hydride in toluene (30 mlof 1M) was added dropwise. The mixture was stirred at -78° C. for 1.5hours, then allowed to slowly warm to room temperature. The reaction wasquenched by pouring onto iced dilute acetic acid, the product wasextracted into methylene chloride and the organic extracts were washedwith water, 5% sodium carbonate solution and brine. The dried,concentrated product was a light tan solid (3.32 g). Crystallizationfrom ethanol/water gave1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole; mp98°-101° C.

The title compound was prepared by the procedure of Example 1(iii andiv) using1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole inplace of2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp161°-162° C.

EXAMPLE 47(E)-3-[{1-(2-Chorophenyl)methyl}-2-propenylthio-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound is prepared following the procedure of Example 46using allyl bromide in place of propyl bromide.

EXAMPLE 48(E)-3-[{1-(2-Chorophenyl)methyl}-2-pentylthio-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound is prepared following the procedure of Example 46using 1-bromopentane in place of propyl bromide.

EXAMPLE 49(E)-3-[{1-(2-Chorophenyl)methyl}-2-benzylthio-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound is prepared following the procedure of Example 46using benzyl bromide in place of propyl bromide.

EXAMPLE 50(E)-3-[{1-(2-Chorophenyl)methyl}-2-cyclohexylthio-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound is prepared following the procedure of Example 46using cyclohexyl bromide in place of propyl bromide.

EXAMPLE 51(E)-3-[{1-(2-Chorophenyl)methyl}-2-heptylthio-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound is prepared following the procedure of Example 46using 1-bromoheptane in place of propyl bromide.

EXAMPLE 52(E)-3-[{1-(2-Chorophenyl)methyl}-2-hexenylthio-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound is prepared following the procedure of Example 46using 6-bromo-1-hexene in place of propyl bromide.

EXAMPLE 53(E)-3-[{1-(2-Chorophenyl)methyl}-2-cyclopropylthio-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound is prepared following the procedure of Example 46using cyclopropyl bromide in place of propyl bromide.

EXAMPLE 54(E)-3-[2-n-Butyl-1-{[2-chloro-4-(1H-tetrazol-5-yl]phenyl]methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The procedure of Example 42 is followed using t-butyl4-bromomethyl-3-chlorobenzoate (prepared from 3-chloro-4-methylbenzoicacid by esterification with 2-methylpropene in the presence ofconcentrated sulfuric acid, followed by methyl bromination withN-bromosuccinimide) in place of ethyl 4-bromomethyl-3-chlorobenzoate togive ethyl(E)-3-[2-n-butyl-1-{[2-chloro-4-(carbo-t-butoxy)phenyl]methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate.The t-butyl ester is converted to the corresponding acid compound usingtrifluoroacetic acid.

To a suspension-of ethyl(E)-3-[2-n-butyl-1-{(2-chloro-4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)-methyl-2-propenoatein benzene is added thionyl chloride. The resultant mixture is heated to50° C. for 90 minutes, then evaporated to an oily residue. The residueis taken up in hexane and evaporated again. The acid chloride is treatedwith concentrated ammonium hydroxide and then the reaction mixture isstirred for 16 hours at room temperature. The solid is filtered, washedwith water, and dried at 50° C. under vacuum to yield the primary amidederivative.

To a solution of dimethylformamide in aceto-nitrile is added oxalylchloride at 0° C. under argon. After 3 minutes, a solution of the amideprepared above in dimethylformamide is added via a cannula. Five minuteslater, pyridine is added; the reaction mixture is stirred for anadditional 5 minutes at 0° C. then partitioned between ethyl acetate and50% aqeuous ammonium chloride. The ethyl acetate layer is washed withwater and brine. The ethyl acetate extract is dried with anhydroussodium sulfate and evaporated to give the corresponding nitrilederivative.

Tetrahydrofuran is added under argon with stirring to a mixture of thenitrile prepared above and aluminum chloride. Sodium azide is added allat once, followed by a tetrahydrofuran rinse, and the reaction is heatedto 65° C. for 22 hours, then cooled to room temperature. The reactionmixture is diluted with ethyl acetate and treated with 10% hydrochloricacid solution with vigorous stirring for 5 minutes. The ethyl acetatelayer is washed with water and brine. The ethyl acetate layer is driedwith anhydrous sodium sulfate and evaporated to give ethyl(E)-3-[2-n-butyl-1-{[2-chloro-4-(1H-tetrazol-5-yl)phenyl]methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate.

The title propenoic acid compound is prepared from the above ethyl esterby basic hydrolysis using aqueous base in methanol.

EXAMPLE 55(E)-[2-n-Butyl-1-{(2-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 1using 2-nitrobenzyl bromide in place of 2-chlorobenzyl bromide; mp205°-206° C.

EXAMPLE 56(E)-[2-n-Butyl-1-{(3-nitrophenyl)methyl}-1H-imidazol-5yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 1using 3-nitrobenzyl alcohol in place of 2-chlorobenzyl alcohol; mp182°-184° C.

EXAMPLE 57(E)-[2-n-Butyl-1-{(4-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 42using 4-nitrobenzyl bromide in place ofethyl-4-bromomethyl-3-chlorobenzoate; mp 198°-200° C.

EXAMPLE 58(E)-[2-n-Butyl-1-{(2-trifluoromethylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 1using 2-trifluoromethylbenzyl alcohol in place of 2-chlorobenzylalcohol; mp 202°-203° C.

EXAMPLE 59(E)-[2-n-Butyl-1-{(2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 1using 2,3-dichlorobenzyl alcohol in place of 2-chlorobenzyl alcohol; mp184°-185° C.

EXAMPLE 60(E)-[2-n-Butyl-1-{(3-methoxy-2-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 42using 3-methoxy-2-nitrobenzyl bromide in place of ethyl4-bromomethyl-3-chlorobenzoate; mp 213°-215° C.

EXAMPLE 61(E)-[2-n-Butyl-1-{(2-cyanophenyl)methyl}-1H-imidazol-5-yl]-2-{2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 1using 2-cyanobenzyl bromide in place of ethyl4-bromomethyl-3-chlorbenzoate; mp 210°-212° C.

EXAMPLE 62(E)-[2-n-Butyl-1-{(4-methoxy-3-methylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 42using 4-methoxy-3-methylbenzyl bromide in place of ethyl4-bromomethyl-3-chlorobenzoate; mp 140°-141° C.

EXAMPLE 63(E)-[2-n-Butyl-1-{(3-methoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 1using 3-methoxybenzyl alcohol in place of 2-chlorobenzyl alcohol; mp170°-171° C.

EXAMPLE 64(E)-[2-n-Butyl-1-{(2-methoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 1using 2-methoxybenzyl alcohol and methanesulfonic anhydride in place of2-chlorobenzyl alcohol and triflic anhydride; mp 186°-187° C.

EXAMPLE 65(E)-[2-n-Butyl-1-{(2-hydroxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared from the 2-methoxy compound prepared inExample 64 using boron tribromide in methylene chloride; 181°-183° C.

EXAMPLE 66(E)-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methoxy-2-thienyl)methyl-2-propenoicAcid

The title compound was prepared by the procedure of Example 1 using3-(5-methoxy-2-thienyl)-2-phosphonopropionate in place of3-(2-thienyl)-2-phosphonopropionate; mp 184°-185.5° C.

EXAMPLE 67(E)-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-methoxy-2-thienyl)methyl-2-propenoicAcid

The title compound was prepared by the procedure of Example 1 using3-(4-methoxy-2-thienyl)-2-phosphonopropionate in place of3-(2-thienyl)-2-phosphonopropionate; mp 170°-171° C.

EXAMPLE 68(E)-3-[2-n-Hexyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 1,using caproylamidine methyl ether hydrochloride in place of valeramidinemethyl ether hydrochloride and using 4-carbomethoxybenzyl alcohol inplace of 2-chlorobenzyl alcohol; mp 210°-212° C.

EXAMPLE 69(E)-3-[2-n-Propyl-1-{(2-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 1using butyramidine methyl ether hydrochloride in place of valeramidinemethyl ether hydrochloride and 2-nitrobenzyl alcohol in place of2-chlorobenzyl alcohol; mp 223° C.

EXAMPLE 70(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-[1-phenyl-1-(2-thienyl)phenylmethyl]-2-propenoicAcid

The title compound was prepared using the procedure of Example 1 (i, ii,iii, iv [Method B]) replacing methyl 3-(2-thienyl)propanoate with methyl3-phenyl-3-(2-thienyl)propanoate [prepared as in Tetra. 44(7) 2055(1988)]; mp 204°-206° C.

EXAMPLE 71(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-[2-phenyl-1-(2-thienyl)ethyl]-2-propenoicAcid

The title compound was prepared using the procedure of Example 1 (i, ii,iii, iv [Method B]) replacing methyl 3-(2-thienyl)propanoate with methyl3-benzyl-3-(2-thienyl)propanoate [prepared following the proceduredescribed in Tetra. 44 (7) 2055 (1988)]; mp 200°-202° C.

EXAMPLE 72(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-{1-(2-thienyl)pentyl}-2-propenoicAcid

The title compound was prepared using the procedure of Example 1 (i, ii,iii, iv [Method B]) replacing methyl 3-(2 -thienyl) propanoate withmethyl 3-(2-thienyl)heptanoate; mp 161°-163° C.

EXAMPLE 73E-3-[2-n-Butyl-1-{(2-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared using the procedure of Example 42replacing ethyl 4-bromomethyl-3-chlorobenzoate with ethyl2-bromomethylbenzoate; 201°-202° C.

EXAMPLE 74E-3-[2-n-Butyl-1-{(3-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared by the procedure of Example 1 (iv,Method B) using2-n-butyl-1-[(4-carbomethoxyphenyl)methyl]imidazole-5-aldehyde (preparedby the method described for the preparation of2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehydein Example 42) and methyl 3-(2-thienyl)propanoate; mp 243°-244° C.

EXAMPLE 75(E)-3-[2-n-Butyl-1-{(4-hydroxy-3-methylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared by demethylation of(E)-2-n-butyl-1-{(4-methoxy-3-methylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid, prepared in Example 62, using boron tribromide in methylenechloride; mp 150°-152° C.

EXAMPLE 76(E)-3-[2-n-Butyl-1-{(4-carbomethoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared using2-n-butyl-1-[(4carbomethoxyphenyl)methyl]imidazole-5-aldehyde (preparedby the method described for the preparation of2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehydein Example 42) and t-butyl 3-(2-thienyl)-propanoate by the procedure ofExample 1 (iv, Method B), except, instead of basic hydrolysis,trifluoroacetic acid hydrolysis of the t-butyl ester was employed; mp217°-220° C.

EXAMPLE 77(E)-3-[2-n-Butyl-1-{(4-cyanophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared using2-n-butyl-[(4cyanophenyl)methyl]imidazole-5-aldehyde (prepared by themethod of Example 42 describing the preparation of2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehyde)and methyl 3-(2-thienyl)propanoate by the procedure of Example 1 (iv,Method B), except, instead of basic hydrolysis of the ester with sodiumhydroxide, potassium carbonate hydrolysis was employed; mp 190°-192° C.

EXAMPLE 78(E)-3-[2-n-Butyl-1-{(4-carbamoylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

Methyl(E)-3-[2-n-butyl-1-{(4-cyanophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propanoate,prepared in Example 77, was subjected to hydrolysis with concentratedhydrochloric acid to give the title compound; mp 210°-212° C.

EXAMPLE 79(E)-3-[2-n-Butyl-1-{[4-(1H-tetraol-5-yl)-phenyl]methyl}-1H-imidazol-5-yl]-2-(2-thienyl)-methyl-2-propenoicAcid

The title compound was prepared from methyl(E)-3-[2-n-butyl-1-{(4-cyanophenyl)methyl}-1H-imidazol-5yl]-2-(2-thienyl)methyl-2-propanoate,prepared in Example 77, using the procedure described in Example 54; mp246°-248° C.

EXAMPLE 80(E)-3-[2-n-Propyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared using the procedure of Example 1replacing valermamidine methyl ether hydrochloride with butyramidinemethyl ether hydrochloride and replacing 2-chlorbenzyl alcohol with4-carbomethoxybenzyl alcohol; mp 250° C. (d).

EXAMPLE 81(E)-3-[2-n-Propyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared using the procedure of Example 1replacing valeramidine methyl ether hydrochloride with butyramidinemethyl ether hydrochloride; mp 200° C.

EXAMPLE 82(E)-3-[2-n-Hexyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared using the procedure of Example 1replacing valeramidine methyl ether hdyrochloride with caproylamidinemethyl ether hydrochloride; mp 161°-163° C.

EXAMPLE 83(E)-3-[2-n-Butyl-1-{(4-carboxy-2,3-dichlorophenylmethyl}1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

(i) methyl 2,3-dichloro-4-methylbenzoate

Chlorine was bubbled into a suspension of 17.2 g of ferric chloride in1516 g of p-xylene until the mixture contained 40.5%2-chloro-1,4-xylene, 43% 2 5-dichloro-1,4-xylene, and 16.5%2,3-dichloro-1,4-xylene as monitored by gas chromatography. Distillationat 15 mmHg gave 710 g of a fraction with a boiling point of 95°-106°which was 30-40% 2,3-dichloro-1,4-xylene. Trituration with isopropanolfollowed by concentration of the isopropanol solution gave 360 g ofproduct which contained 45% of 2,3-dichloro-1,4-xylene. Reflux of 251 gof this with 3.5 liters of 45% nitric acid for 23 hours followed byquenching in 3 liters of ice water gave a solid which was dissolved in6.4% aqueous potassium hydroxide solution. This was extracted twice withethyl acetate. Acidification of the aqueous solution gave a solid whichwas dissolved in 3200 mL of methanol containing 50 mL of concentratedsulfuric acid and refluxed for 18 hours. The reaction mixture wasconcentrated under vacuum, diluted with water, and extracted with ethylacetate. Concentration gave an oil which still contained some acid sothe esterification was repeated to give 198 g of mixed esters (39%2,5-dichloro- and 52% 2,3-dichloro-1,4-xylene). Repeated chromatography(silica gel, mobile phase 80:20 hexanemethylene chloride) of the crudemixture gave 53 g of material which contained 98% of methyl2,3-dichloro-4-methylbenzoate.

(ii) methyl 4-bromomethyl-2,3-dichlorobenzoate

A mixture of 40 g (0.183 mol) of methyl 2,3-dichloro-4-methylbenzoate,34.17 g (0.192 mol) of N-bromosuccinimide, 0.4 g (0.0017 mol) ofbenzoylperoxide, and 640 mL of carbon tetrachloride was stirred at roomtemperature while being irradiated with a 150 watt flood lamp for 2.5hours. Concentration of the filtered reaction mixture under vacuum gave54 g of material which on trituration with pentane followed by storageof the slurry at 5° C. for 18 hours gave 34.6 g (63.5%) of product; mp57°-61° C.

(iii) methyl4-[(2-butyl-5-formyl-4-iodo-1H-imidazol-1-yl)methyl]-2,3-dichlorobenzoate

A suspension of 26.7 g (0.096 mol) of2-butyl-4-iodoimidazole-5-carboxaldehyde (prepared in Example 96 (i) and(ii)) and 28.01 g (0.203 mol) of dry potassium carbonate in 350 mL ofdimethylformamide was stirred under argon for 20 minutes. Then 30 g(0.10 mol) of methyl 4-bromothyl-2,3-dichlorobenzoate was added and themixture was stirred at 80° C. for 1.5 hours. The reaction mixture waspoured into water and extracted several times with ether. Filtration ofthe solid formed at the ether-water interface gave 19.35 g of product.The ether layer was washed 4 times with water, once with brine, and thenconcentrated under vacuum to give a solid. Recrystallization of thecombined solids from methanol gave 32.55 g (68%) of product; mp135°-137° C.

(iv) methyl4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]-2,3-dichlorobenzoate

A suspension of 34.2 g (0.069 mol) of methyl4-[(2-butyl-5-formyl-4-iodo-1H-imidazol-1-yl)methyl]-2,3-dichlorobenzoateand 6.84 g of 10% palladium on carbon in 850 mL of ethyl acetate wasshaken under hydrogen at 3 Torr for 1 hour. The mixture was filteredthrough Celite® and concentrated under vacuum to 300 mL. This solutionwas washed in turn with 5% sodium carbonate solution, water, and brineand then concentrated to an oil which crystallized on standing. This wasdissolved in 25 mL of hot methanol which when cooled gave crystals. Thesuspension was slowly diluted with water and then filtered to give 24.39g (96%) of crystals; mp 94°-96° C.

(v) methyl(E)-3-[2-n-butyl-1-{(4-carbomethoxy-2,3-dichlorophenyl)methyl}-1H-imidazole-5-yl]-2-(2-thienyl)methyl-2-propanoate

A mixture of 19.0 g (0.051 mol) of methyl4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]-2,3-dichlorobenzoate 47.6g (0.208 mol) of 2-carbethoxy-3-thienylpropinonic acid, 2.19 g (0.026mol) of piperidine, and 900 mL of benzene was heated under reflux for 18hours using a Dean-Stark trap to remove water. An additional 13.33 g(0.058 mol) of the thienylpropionic acid was added and the refluxing wascontinued for 5 hours; another 26.6 g (0.116 mol) of ester and 1 mL ofpiperidine was added and the refluxing continued for an additional 18hours. Concentration of the reaction mixture under vacuum gave a syrupwhich was dissolved in ether and then made acidic with etherealhydrochloric acid. The resulting solid was collected by filtration andwashed with ether to give 20.05 g (68%) of crystals; mp 165°-166° .

(vi)(E)-3-[2-n-butyl-1-{(4-carboxy-2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propanoicacid

A mixture of 19.5 g (0.034 mol) ofmethyl(E)-3-[2-n-butyl-1-{(4-carbomethoxy-2,3-dichlorophenyl)methyl}-1H-imidazole-5-yl]-2-(2-thienyl)methyl-2-propanoateand 9.60 g (0.24 mol) of sodium hydroxide, 100 mL of ethanol and 100 mLof eater was heated on a steam bath to form a homogeneous solution whichwas then stirred at 25° C. for 18 hours. The mixture was concentrated ona steam bath to 100 mL, filtered, and diluted with 150 mL of water. ThepH was brought to 3.38 with 10% hydrochloric acid solution. Theresulting solid was collected by filtration. The solid was suspended in350 mL of acetone which was heated to reflux and 200 mL of water wasadded slowly. The mixture concentrated to 300 mL. Chilling andfiltration gave a solid which was washed with water and dried at 90° C.under vacuum (0.5 mmHg) to give 15.35 g (91%) of the title compound; mp245°-247° C.

EXAMPLE 84(E)-3-[2-n-Butyl-1-{(4-carboxy-2,5-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic Acid

The title compound was prepared using the procedure of Example 42replacing ethyl 4-bromomethyl-3-chlorobenzoate with methyl4-bromomethyl-3,6-dichlorobenzoate (prepared by oxidation of2,5-dichloro-p-xylene with nitric acid, followed by esterification withmethanol/hydrochloric acid, and methyl bromination withN-bromosuccinimide); mp 145° C.

EXAMPLE 85(E)-3-[2-n-Butyl-1-{(4-carboxynaphth-1-yl)methyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

(i) 2-butyl-5-hydroxymethyl-4-iodoimidazole

N-Iodosuccinimide (148.75 g, 0.661 mol) was added to a stirred solutionof 2-butyl-4-hydroxymethylimidazole (100.78 g, 0.652 mol) in 500 mL ofabsolute ethanol. After 20 minutes the solution was heated to 40°-45° C.for 45 minutes, diluted with 2.5 liters of water, and chilled. Thecrystalline product was collected by filtration, washed with water, anddried to give 174.5 g (95%) of crystals; mp 166°-166.5° C.

(ii) 2-butyl-4-iodoimidazol-5-carboxaldehyde

A stirred mixture of 174.1 g (0.62 mol) of2-butyl-5-hydroxymethyl-4-iodoimidazole and 360 g (4.14 mol) ofmanganese dioxide in 3 liters of methylene chloride was refluxed for 24hours using a trap to remove water. The hot reaction mixture wasfiltered through Celite® which was then washed with 4.5 liters ofboiling methylene chloride. The combined filtrates were concentrated todryness, the residue was dissolved twice in 150 mL of methanol and thesolution was concentrated to dryness. The residue was dissolved in 130mL of methanol and chilled. After crystallization had occurred, 700 mLof water was added slowly. The mixture was chilled, the solid wascollected by filtration, and washed with water to give 145.2 g (84%) ofproduct; mp 104°-105° C.

(iii)methyl-4-[(2-butyl-5-formyl-4-iodo-1H-imidazol-1-yl)methyl]naphthalene-1-carboxylate

A suspension of 29.53 g (0.214 mol) of powdered potassium carbonate,60.00 g (0.214 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde and65.68 g (0.235 mol) of methyl 4-bromomethylnaphthalene-1-carboxylate (E.A. Dixon, A. Fischer, and F. P. Robinson, Can. J. Chem, 59, 2629 (1981))in 600 mL of dimethylformamide was stirred for 5 hours under argon at70° C. An additional 6.56 g (0.0235 mol) of the bromomethyl ester wasadded and the suspension was stirred an additional 15 hours at 70° C.The reaction mixture was poured into water and the resulting solid wascollected by filtration, washed with water, and triturated several timeswith 250 mL of boiling methanol to give 86.8 g (85%) of a solid; mp177.5°-179° C.

(iv)methyl-4-[(2-butyl-5-formyl-1H-imidazol-1-yl)-methyl]naphthalene-1-carboxylate

A suspension of 40.0 g (83.9 mmol) ofmethyl-4-[(2-Butyl-5-formyl-4-iodo-1H-imidazol-1-yl)methyl]naphthalene-1-carboxylate,9.07 g (92.4 mmol) of potassium acetate, and 6.0 g of 10% palladium oncarbon in 1.2 liters of ethyl acetate was hydrogenated for 2 hours. Thesolids were removed by filtration and an additional 8.0 g of 10%palladium on carbon and 9.01 g (92.4 mmol) of potassium acetate wasadded. After hydrogenating the reation mixture an additional 2 hours,the solids were removed by filtration and the solution was concentratedto about 1/3 volume. The ethyl acetate solution was washed with aqueoussodium carbonate solution, dried over magnesium sulfate, andconcentrated under vacuum to give an oil which crystallized.Recrystallization from methylene chloride-hexane gave 25.77 g (87.6%) ofcolorless crystals; mp 95.5°-97° C.

(v) methyl(E)-3-[2-n-butyl-1-{(4-carbomethoxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate

The title compound from 25.0 g ofmethyl-4-[(2-Butyl-5-formyl-1H-imidazol-1-yl)-methyl]naphthalene-1-carboxylate the procedure of Example 20 to give 22.12 g(56%) of product as the hydrochloride salt; mp 217°-218° C.

(vi)(E)-3-[[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methylpropenoicacid

A slurry containing 14.46 g (26.14 mmol) of methyl(E)-3-[2-n-butyl-1-{(4-carbomethoxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate, 8.38 g (2.09mmol) of potassium hydroxide in a mixture of 165 mL of ethanol and 85 mLof water was stirred at ambient temperature for 18 hours. Concentrationunder vacuum and dilution with water gave 400 mL of a clear solution.Adjustment of the pH to 4.03 with hydrochloirc acid gave crystals whichwhen recrystallized from methanol gave 9.89 g (80%) of colorlesscrystals; mp 218°-219° C. as a partial hydrate.

EXAMPLE 86(E)-3-[2-n-Butyl-1-{(2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenamide

(E)-3-[2-n-Butyl-1-{(2,3-dichlorophenyl)methyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid, prepared in Example 59, was treated with thionyl chloride and thenammonium hydroxide, as described in Example 54, to give the titlecompound; mp 185°-187° C.

EXAMPLE 87(E)-3-[2-n-Butyl-1-{(4-carbamoylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenamide

(E)-3-[2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid, prepared in Example 41, was treated with thionyl chloride and thenammonium hydroxide, as described in Example 54, to give the titlecompound; mp 204°-206° C.

EXAMPLE 88(E)-3-[2-n-Butyl-1-{(2-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenamide

(E)-3-[2-n-Butyl-1-{(2-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid, prepared in Example 55, was treated with thionyl chloride and thenammonium hydroxide, as described in Example 54, to give the titlecompound; mp 183°-185° C.

EXAMPLE 89E-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)-methyl-2-propenoxyAcetic Acid

To a suspension of sodium hydride (53 mg, 2.3 mmol) in 5 mL of glyme wasadded portionwise (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenol (0.802 mg, 2.0mmol, prepared as described in Example 17). After stirring for 30minutes, methyl bromoacetate (3.35 mg, 2.2 mmol) was added dropwise. Thereaction was stirred overnight at room temperature and then the mixturewas poured into ice-water. The product was extracted into ethyl acetate(3×). The combined organic extracts were washed with water and brine anddried with anhydrous magnesium sulfate. The solvent was removed invacuo. The residue was chromatographed on silica gel eulting withhexane/ethyl acetate (4:6) to give 2.44 mg (26%) of the ester of thetitle compound as an oil.

The ester was saponified by base as described in Example 1, iv, MethodA(c); mp 141°-142° C. (ethyl acetate/methanol).

EXAMPLE 90E-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenylGlycine

To a solution of(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid (0.5 g, 1.2 mmol prepared in Example 1) intetrahydrofuran (12 mL)was added N-hydroxysuccinimide (0.153, 1.33 mmol), followed bydicyclohexylcarbodiimide (0.249 g, 1.2 mmol) in 5 mL of tetrahydrofuran.The reaction mixture was heated at 35° C. for one hour and then glycinemethyl ester hydrochloride (0.197 g, 1.57 mmol) and triethylamine (0.22mL, 1.57 mmol) were added. The reaction was stirred at room temperatureovernight. The mixture was diluted with 20 mL of ethyl acetate and thesolids were filtered. The filtrate was concentrated to dryness and theresidue was chromatographed on silica gel eluting with ethyacetate/hexane (4:6) to give 0.258 g (44%) of the esteramide as an oil.

The ester was saponified to the title acid compound by base, asdescribed in Example 1 (iv, Method A(c); mp 175°-177° C.

EXAMPLE 91(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenamide

(E)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid, prepared in Example 1, was treated with thionyl chloride and thenammonium hydroxide, as described in Example 54, to give the titlecompound; mp 184°-185° C.

EXAMPLE 92(E)-3-[2-n-Butyl-1-{(2-trifluoromethylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenamide

(E)-3-[2-n-Butyl-1-{(2-trifluoromethylphenyl)-methyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid, prepared in Example 58, was treated with thionyl chloride and thenammonium hydroxide, as described in Example 54, to give the titlecompound; mp 207°-208° C.

EXAMPLE 93 Ethyl(E)-3-[2-n-butyl-1-{(4-carbomethoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propanoate

The title compound was prepared following the procedure of Example 1(iv, Method B) using2-n-butyl-1-[(4-carbomethoxyphenyl)methyl]imidazole-5-aldehyde, preparedby the method described for the preparation of2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehydein Example 42, and ethyl 3-(2-thienyl)propanoate; mp 130°-132° C.

EXAMPLE 94(E)-3-[2-n-Butyl-1-{(4-carboxyphenyl)ethyl}-1H-imidazo-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 42,replacing2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methy]imidazole-5-aldehydewith 2-n-butyl-1-[(4-carboethoxyphenyl)ethyl]imidazole-5-aldehyde; mp256°-259° C.(d).

EXAMPLE 95(E)-3-[2-n-Butyl-1-{4-carboxyphenyl}-1H-imidazo-5-yl]-2-(2-theinyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 42replacing2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methy]imidazole-5-aldehydewith 2-n-butyl-[(4-carboethoxyphenyl]imidazole-5-aldehyde; mp 260°-265°C.(d).

EXAMPLE 96(E)-3-[2-n-Butyl-1-{(3,4-dicarboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 20replacing methyl 3-(4-pyridyl) propanoate with methyl3-(2-thienyl)propanoate and2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde with2-n-butyl-1-(3,4-dicarbomethoxyphenyl)methyl}-1H-imidazol-5-carboxaldehyde; mp 204°-205° C.

EXAMPLE 97(E)-3-[2-n-Butyl-1-{4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)ethyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 20replacing methyl 3-(4-pyridyl)propanoate with methyl4-(2-thienyl)butanoate and2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde with2-n-butyl-1-)4-carbomethoxyphenyl) methyl-1H-imidazol-5-carboxaldehyde;mp 244°-246° C.(d).

EXAMPLE 98(E)-3-[2-n-Butyl-1-{(4-carboethoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 42replacing2-n-butyl-1-[(4-carbomethoxy-2-chlorophenyl)methyl]imidazole-5-aldehydewith 2-n-butyl-1-[(4-carboethoxyphenyl)methyl]imidazole-5-aldehyde ethyl2-carboxy-3-(2-thienyl)propionate and potassium hydroxide inwater-ethanol at ambient temperature with lithium chloride indimethylformamide at 80°-125° C.; mp 129°-131° C. (d).

EXAMPLE 99(E)-3-[2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenyl.Glycine

The title compound was prepared following the procedure of Example 90replacing(E)-3-[2-n-butyl-1-{2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid with(E)-3-[2-n-butyl-1-{(4-carboethoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid, prepared in Example 98; mp 223°-224 ° C.

EXAMPLE 100(E)-3-[2-n-Butyl-1-{(4-carboxymethylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 42replacing ethyl 4-bromomethyl-3-chlorobenzoate with 4-bromomethylphenylacetic acid, methyl ester; mp 169°-171° C.

EXAMPLE 101(E)-3-[2-n-Butyl-1-{(4-carboxymethoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 42replacing ethyl 4-bromomethyl-3-chlorobenzoate with4-bromomethylphenoxyacetic acid, methyl ester; mp 192°-194° C.

EXAMPLE 102(E)-3-[2-n-Butyl-1-{4-carboxy-3-hydroxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

(i) methyl 4-methylsalicylate

To a suspension of 10 g (0.0651 mol) of 4-methylsalicylic acid in 150 mLof methanol was added 50 mL of ethereal hydrochloric acid. The reactionmixture was heated at 60° C. for 60 hours. The solvent was removed undervacuum. After adding hexane-ethyl acetate, the resulting solid wasfiltered and the filtrate was evaporated to give 10.2 g (94%) of productas an oil.

(ii) methyl 2-methoxymethoxy-4-methylbenzoate

To a suspension of sodium hydride (1.62 g, 0.0675 mol) in 90 mL ofdimethylformamide was added dropwise a solution of methyl4-methylsalicylate (10.2 g, 0.0614 mol) in 20 mL of diethyl ether. Afterstirring for 15 minutes, a solution of chloromethyl methyl ether (5.6mL, 0.0737 mol) in 10 mL of diethyl ether was added. The reactionmixture was stirred at room temperature for 18 hours and then it waspartitioned between water and diethyl ether. The layers were separatedand the aqueous layer was extracted an additional three times withdiethyl ether. The combined organic extracts were washed with brine,dried with magnesium sulfate, and concentrated in vacuo to give 14.5 gof an oil. The product was purified by flash chromatography on silicagel eluting with 10%-15% ethyl acetate in hexane to give 9.41 g (73%) ofproduct as an oil.

(iii) methyl 4-bromomethyl-2-methoxymethoxybenzoate

To a solution of methyl 2-methoxymethoxy-4-methylbenzoate (9.41 g,0.0448 mol) in 150 mL of carbon tetrachloride was addedN-bromosuccinimide (7.97 g, 0.0448 mol) and benzoyl peroxide (0.45 g,0.002 mol). The reaction mixture was refluxed for 18 hours. The solidwas filtered and the filtrate was concentrated in vacuo to give 13.2 gof an oil. The product was purified by flash chromatography on silicagel eluting with 20% ethyl acetate in hexane to give 10.2 g (79%) ofproduct as an oil.

(iv)2-n-butyl-1-(4-carbomethoxy-3-methoxymethoxyphenylmethyl-4-chloro-1H-imidazol-5-carboxaldehyde

To a solution of 2-n-butyl-4-chloro-1H-imidazol-5-carboxaldehyde (2.0 g,10.7 mmol) in 25 mL of dimethylformamide was added potassium carbonate(1.78 g, 12.9 mmol). The suspension was stirred at 45° C. for 15 minutesand then methyl 4-bromomethyl-2-methoxymethoxybenzoate was added. Thereaction mixture was stirred at 60° C. for 2 hours and then it waspartitioned between ice water and ethyl acetate. The layers wereseparated and the aqueous layer was extracted a second time with ethylacetate. The combined organic extracts were washed with brine, driedwith magnesium sulfate, and concentrated in vacuo. The product waspurified by flash chromatography on silica gel eluting with 30% ethylacetate in hexane to give 3.28 g (78%) of product as an oil.

(v)2-n-butyl-1-(4-carbomethoxy-3-methoxymethoxyphenyl)methyl-1-H-imidazol-5-carboxaldehyde

To a suspension of 0.32 g of 10% palladium on carbon in 15 mL ofmethanol containing potassium acetate (0.813 g, 8.28 mmol) was added asolution of2-n-butyl-1-(4-carbomethoxy-3-methoxymethoxyphenyl)methyl-4-chloro-1H-imidazol-5-carboxaldehyde(3.27 g, 8.28 mmol) in 60 mL of methanol. The reaction was hydrogenatedat 4 psi for 40 minutes. The solid was filtered and the filtrate wasconcentrated in vacuo. The residue was partitioned between diethyl etherand water. The pH of the aqueous layer was adjusted to 7.5 with 5%sodium carbonate solution. The layers were separated and the organiclayer was washed with brine and dried with magnesium sulfate. Thesolvent was removed in vacuo to give 2.59 g (87%) of product as an oil.

(vi) methyl(E)-3-[2-n-butyl-1-{(4-carbomethoxy-3-methoxymethoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate

The title compound was prepared following the procedures of Example 1,Method B, (a)-(c) replacing2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde with2-n-butyl-1-(4-carbomethoxy-3-methoxymethoxyphenyl)-methyl-1H-imidazol-5-carboxaldehyde.The product was isolated as an oil.

(vii) methyl(E)-3-[2-n-butyl-1-{(4-carbomethoxy-3-hydroxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate

To a solution of methyl(E)-3-[2-n-butyl-1-{(4-carbomethoxy-3-methoxymethoxyphenyl)methyl{-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate(2.1 g, 4.1 mmol) in 40 mL of methanol was added approximately 0.1 mL ofconcentrated hydrochloric acid. The reaction was refluxed for 5 hoursand then concentrated in vacuo. The residue was partitioned betweenethyl acetate and saturated sodium bicarbonate solution. The layers wereseparated. The organic extract was dried with magnesium sulfate, and thesolvent was removed in vacuo to give 1.76 g (92%) of product as an oil.

(viii) (E)-3-[2-n-butyl-1-{(4-carboxy-3-hydroxyphenyl)methyl1}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate

The title compound was prepared following the procedure of Example 1,Method A (c); mp 192.5°-194° C.

EXAMPLE 103(E)-3-[2-n-Butyl-3{2-carboxybiphenyl-5-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 102,using methyl 4-bromomethyl-2-phenylbenzoate in place of methyl4-bromomethyl-2-methoxymethoxybenzoate; mp 158°-161° C. (hydrochloricacid salt).

EXAMPLE 104(E)-3-[2-n-Butyl-1-{(4-carboxyethenylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 42replacing2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehydewith2-n-butyl-1-[(4-carbomethoxyethenylphenyl)methyl]imidazole-5-aldehyde;mp 199°-203° C.

EXAMPLE 105(E)-3-[2-n-Butyl-1-{(4-carboxyethylphenyl)methyl}-1H-imidazol-5-yl]-2-2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 42replacing2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehydewith2-n-butyl-1-[(4-carbomethoxyethylphenyl)methyl-1H-imidazole-5-aldehyde;mp 179°-182° C.

EXAMPLE 106(E)-3-[2-(2-phenylethyl)-1-{(4-carboxyphenyl)methyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicAcid

The title compound was prepared following the procedure of Example 1; mp213.5°-214.5° C.

EXAMPLE 107(E)-3-[2-(3-methylbutyl)-1-[(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-3-propenoicAcid

The title compound was prepared following the procedure of Example 1; mp251.5°-252° C.

EXAMPLE 108

An oral dosage form for administering orally active Formula (I)compounds is produced by screening, mixing and filling into hard gelatincapsules the ingredients in proportions, for example, as shown below.

    ______________________________________                                        Ingredients         Amounts                                                   ______________________________________                                        (E)-3-[2-n-butyl-1-{(4-                                                                           100 mg                                                    carboxyphenyl)methyl}-1H-                                                     imidazol-5-yl]-2-(2-                                                          thienyl)methyl-2-propenoic                                                    acid                                                                          magnesium stearate   10 mg                                                    lactose             100 mg                                                    ______________________________________                                    

EXAMPLE 109

The sucrose calcium sulfate dihydrate and orally active Formula (I)compounds are mixed and granulated with a 10% gelatin solution. The wetgranules are screened, dried, mixed with the starch, talc and stearicacid, screened and compressed into a tablet.

    ______________________________________                                        Ingredients        Amounts                                                    ______________________________________                                        (E)-3-[2-n-butyl-1-{(4-                                                                          75 mg                                                      carboxy-2-chlorophenyl)-                                                      methyl}-1H-imidazol-5-yl]-                                                    2-(2-thienyl)methyl-2-                                                        propenoic acid                                                                calcium sulfate dihydrate                                                                        100 mg                                                     sucrose            15 mg                                                      starch             8 mg                                                       talc               4 mg                                                       stearic acid       2 mg                                                       ______________________________________                                    

EXAMPLE 110

(E)-3-[2-n-Butyl-1-{(4-carboxy-3-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid, 50 mg, is dispersed in 25 mL of normal saline to prepare aninjectable preparation.

EXAMPLE 111

A topical opthamological solution for administering Formula (I)compounds is produced by mixing under sterile conditions the ingredientsin proportions, for example, as shown below.

    ______________________________________                                                           Amounts                                                    Ingredients        (mg/mL)                                                    ______________________________________                                        (E)-3-[2-n-butyl-1-{2-                                                                           1.0                                                        chlorophenyl)methyl}-1H-                                                      imidazol-5-yl]-2-(2-                                                          thienyl)methyl-2-propenoic                                                    acid                                                                          dibasic sodium phosphate                                                                         10.4                                                       monobasic sodium phosphate                                                                       2.4                                                        chlorobutanol      5.0                                                        hydroxypropanol                                                               methylcellulose    5.0                                                        sterile water      q.s.ad 1.0 mL                                              1.0 N sodium hydroxide                                                                           q.s.ad pH 7.4                                              ______________________________________                                    

It is to be understood that the invention is not limited to theembodiments illustrated hereabove and the right to the illustratedembodiments and all modifications coming within the scope of thefollowing claims is reserved.

What is claimed is:
 1. A compound which is(E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a pharmaceutical carrier and(E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid.
 3. A method of antagonizing angiotensin II receptors whichcomprises administering to a subject in need thereof an effective amount(E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid.
 4. A method of treating hypertension which comprises administeringto a subject in need thereof an effective amount of(E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid.
 5. A method of treating congestive heart failure which comprisesadministering to a subject in need thereof an effective amount of(E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid.
 6. A method of treating renal failure which comprisesadministering to a subject in need thereof an effective amount of(E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid.
 7. A method of treating glaucoma which comprises administering toa subject in need thereof an effective amount of(E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoicacid.